- Review
- Open access
- Published:
Advances in targeting cancer-associated fibroblasts through single-cell spatial transcriptomic sequencing
Biomarker Research volume 12, Article number: 73 (2024)
Abstract
Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment and are related to tumor proliferation, metastasis, relapse, and drug resistance. With the development of sequencing technologies, single-cell RNA sequencing has become a popular method for identifying CAFs in the tumor microenvironment. Whereas the drawbacks of CAFs, such as the lack of a spatial landscape, still exist, recent research has utilized spatial transcriptomics combined with single-cell RNA sequencing to address this issue. These multiomics analyses can resolve the single-cell resolution problem in spatial transcriptomics. In this review, we summarized the recent literature regarding the targeting of CAFs to address drug resistance, angiogenesis, metabolic reprogramming and metastasis in tumor tissue.
Background
With respect to tumor initiation, a considerable number of studies is associated with the “seed and soil” hypothesis proposed by Stephen Paget over a century ago [1]. The last two decades have seen a growing trend toward the tumor microenvironment, which is one of the most frequently noted factors in tumor development, proliferation, metastasis, and relapse.
There are many components of the tumor microenvironment, such as tumor infiltrating lymphocytes (TILs), natural killer cells, tumor infiltrating dendritic cells (TIDCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), distinct proangiogenic factors and immune checkpoint biomarkers [2]. Traditionally, CAFs have been thought to interact with the cancer cells, having tumor-promoting effects; however, accumulating evidence indicates that CAFs have the apparent tumor-suppressive functions [3, 4]. Moreover, among the whole subgroup of the tumor environment, CAFs account for almost 70% [5], and they can also participate in extracellular matrix remodeling, chemoresistance; radio-resistance; immune evasion and modulation; angiogenesis; and metabolism by secreting various of chemokines, exosomes, cytokines and other effector molecules [6,7,8].
Increased knowledge of their proportion, heterogeneity, and origin, among other information, at the individual cell level would contribute to a deeper understanding of CAFs. Like separating individual components of a salad, single-cell RNA sequencing (scRNA-seq) can dissociate whole tissues into individual cells [9, 10]. However, this technology does not provide spatial information or address cross-talk in the TME. Therefore, after the wave of single-cell analysis, spatial transcriptomics (ST) has become an important method in the last decade [9, 11]. In addition to overcoming the limitations of scRNA-seq, ST is better for mapping and exploring different functional regions and intercellular interactions in the TME at the two-dimensional level [12, 13]. With increasing throughput and scale, ST produces large amounts of RNA imaging data, and a newly developed computational framework, Bento, was published for the subcellular analysis of ST data [14]. Recently, whole-transcriptomic digital spatial profiling (DSP) revealed three multicellular colonies in PDAC, i.e., treatment enriched, squamoid/basaloid and classical colonies, providing promising therapeutic targets [15]. For colorectal cancer, combined with the ssGSEA algorithm, ST can be used to determine cell types such as dendritic cells, NK cells, monocytes, and epithelial cells in different regions [16]. In addition, according to an ST analysis, high expression of MMP14 has been shown to be associated with tumor progression, poor prognosis, and CAFs and TAMs in tumor tissue [17]. Moreover, ST results showed that CAFs induce glycoprotein nonmetastatic B (GPNMB), which promotes the invasion and migration of tumors in breast cancer [18]. Overall, the combined application of ST and scRNA-seq to explore CAFs allows not only for spatial distribution mapping but also for an assessment of cellular heterogeneity [19, 20]. (Fig. 1)
Although extensive research involving single-cell analysis has been carried out for the tumor environment, a complete picture with the comprehensive cellular information is lacking. Owing to the proteomic and epigenomic heterogeneity of the tumor environment, comprehensive information obtained through single-cell multiomics is important [21]. Recently, Cle´mence Henon et al. revealed that the EWSR1::WT1 transcription factor is associated with the prognosis of desmoplastic small round cell tumor patients and customized therapies via single-cell multiomics analysis [22]. Technologies based on genetics, transcriptomics and proteomics have expanded rapidly in recent years, and TME targets and tumor cellular biomarkers can be identified directly by advanced clinical therapy [23]. Through scRNA-seq, spatial transcriptomics, proteomics, Junpeng Fan et al. identified that in cervical squamous cell carcinoma, the MP6/7 score was associated with the immunotherapy response [24]. In addition, metabolic pathway related targets and metabolic enzymes can be utilized in advanced therapeutic strategies, while spatially resolved metabolomics methods can be used to identify genes in their native state [25, 26]. Whereas, single-cell multiomics studies have revealed different challenges, mainly in terms of insufficient sample sizes, a lack of validation in different cancer types [22, 24, 26, 27]. Overall, studies have indicated that multiomics analysis is more beneficial for obtaining a comprehensive understanding of cellular process than any single omics analysis is [28, 29].
The TME, as described above, is a key factors in drug resistance, immunotherapy targeting and tumor progression and metastasis. To date, a considerable number of single-cell multiomics studies of the TME have been published. Furthermore, many studies regarding CAFs, which are a hot topic of TME and cancer research, have been conducted [30].
CAFs with angiogenesis
As the hallmark of malignant tumors in solid tissue, many cell types play the significant roles in angiogenesis, such as lymphocytes, NK cells, pericytes, CAFs and TAMs [31]. CAFs secrete proangiogenic factors directly and produce ECM indirectly to regulate angiogenesis.
Proangiogenic factors
Secreted from CAFs, different kinds of cytokines, such as the CXCL family, FGF, WNT2, VEGF, and HGF, promote angiogenesis in solid tumors. Recently, studies have demonstrated that CXCL8(IL-8) is a proangiogenic chemokine in pancreatic cancer and TNBC, playing a role through HUVECs [32, 33]. In addition, CXCL12 is another important angiogenesis-promoting factor in lung cancer, prostate cancer and melanoma. CXCL12 expression is higher in healthy tissue (C-MSCs) than tumor tissue (T-MSCs) [34]. In FAP-positive tumor stromal cells, CXCL12 induced angiogenesis via the CXCL12-CXCR4 axis in melanoma and prostate cancer, findings that were authenticated separately [35, 36]. (Fig. 3C) Moreover, in prostate cancer, NIH-CXCL14 has been shown to stimulate angiogenesis [37].
As one of the proangiogenic factors in CAFs, FGF2 is a promising target for normalizing vessel tubes in lung cancer, breast cancer, melanoma and pituitary tumors [38,39,40,41]. In addition, some studies have indicated that FGF2 regulates angiogenesis through the JAK2/STAT3 signaling pathways in both lung cancer and melanoma [38, 42]. (Fig. 3D) In addition, another study demonstrated that FGF7 promoted angiogenesis in breast cancer cells and HUVECs via crosstalk between CAFs and tumor cells [41].
Like tumor proliferation and invasion, angiogenesis can be induced by ECM stiffness and degradation, and MMP-related pathways play significant roles in the degradation of the ECM around ECs to promote neovessel formation [43]. In addition, MMP11 expression is increased through different pathways in T-MSCs in lung cancer as well as in breast cancer via coculture with mononuclear inflammatory cells [34, 41]. In addition, high expression of MMP9 has been detected in breast cancer, having similar effects as those observed in oral squamous cell carcinoma, and regulates the stimulation of vascularization via the MAPK-AP1 and TAK1-RELA axes [44, 45]. (Fig. 3B)
Secreted from CAFs, both Il-6 and Il-8 are proangiogenic factors, and Il-6 induces proangiogenic effects via the IL-6/STAT3/NF‐κB positive feedback loop in breast cancer and is regulated by WNT2 in CRC [41, 46, 47]. In addition, studies have demonstrated that the Il-8(CXCL8)/CXCR2 axis is involved in tumorigenesis by promoting angiogenesis in metastasized pancreatic cancer and TNBC [32, 33, 48] (Fig. 3A).
As demonstrated by a considerable number of recent studies, vascular endothelial growth factor (VEGF) supports angiogenesis to promote tumor growth [39, 41, 49]. Herein, we summarized the related articles that address downstream VEGF effects, upstream VEGF effects and anti-VEGF effects. VEGF inhibits the expression of apoptotic cytokines and induces enzymes involved in ECM degradation [50]. However, exo-miRNAs promote proangiogenic factor in melanoma and lung cancer via miR-155-5p and by miR-210 via the JAK2/STAT3 signaling pathway, respectively [42, 51]. (Fig. 3D) In colon cancer, VEGFA expression is modulated by CHI3L1, similar to IL-8 secretion, and is altered by p53 status [52, 53]; however, its secretion can be reduced by eicosapentaenoic acid (EPA) during angiogenesis, similar to the ability of EPA to inhibit the secretion of IL-6 [54]. Research on anti-VEGF factors has focused primarily on bevacizumab, which acts against VEGF by neutralizing sEVs [55, 56].
Extracellular matrix (ECM)
Unlike proangiogenic factors, component proteins, such as proteoglycans, periostin, tenascin, fibronectin and collagen, have been shown to increase ECM stiffness and remodel the ECM [57]. Studies have demonstrated that both ATF4 and ProAgio are correlated with angiogenesis in melanoma, lung cancer and breast cancer via the expression of collagen I [58, 59]. (Fig. 3F) In addition, we also reported that tumor angiogenesis involves the TGFβ-fibronectin axis via ECM formation and tumor-fibroblast crosstalk in breast cancer [60, 61] (Fig. 3E).
CAFs with metabolic reprogramming
As the process of changing one cell fate to another, reprogramming affects in tumor progression, metastasis, proliferation and invasion in different cancers. In this review, we summarize advanced research in the following categories: glycolysis reprogramming, amino acid metabolism reprogramming and lipid metabolism reprogramming.
Glycolytic reprogramming
Aerobic glycolysis, also known as the Warburg effect, plays a major role in tumor glucose metabolism in digestive cancer, breast cancer, and lung cancer. Some studies have focused on the reverse Warburg effect in CAFs, and others have focused on lactate utilization in cancer cells [62,63,64,65].
Recently, studies have demonstrated that glycolytic reprogramming in CAFs is involved in tumor progression and heterogeneity in breast cancer via different modes, such as cancer cell-secreted exo-miR-105 promoting MYC expression, cancer cells overexpressing ITGB-4; and normal fibroblasts overexpressing HIF-1α [66,67,68]. In lung cancer, hypoxia-induced exosomal PKM2 regulates the Warburg effect in CAFs, and ROS, TGF-β and GFPT2 reprogram metabolism by increasing aerobic glycolysis [69,70,71]. In addition, we found that the MAPK and ERK1/2 signaling pathways are involved in glycolysis reprogramming in CAFs of oral cancer through H10/miR-675-5p/PFKFB3 and CAV-MCT4/MCT1 respectively [72, 73]. In ovarian cancer, LPA secreted from cancer cell induces aerobic glycolysis reprogramming via NOX1, ROS and HIF1α [74, 75].
In gastric cancer, the LDHA and ENO2 genes as well as ASPN, are related to the reprogramming of the Warburg effect and anaerobic glycolysis, respectively, in cancer cells [76]. In addition, normal fibroblasts reprogram glucose metabolism into aerobic glycolysis and secrete ROS and MCT4 in oral squamous cell carcinoma [77] (Fig. 4).
Amino acid metabolism reprogramming
As major metabolites, amino acids are essential for tumorigenesis and metastasis. Moreover, as a major amino acid, glutamine is essential for metabolic reprogramming [62, 64, 78]. Herein, we summarize recent studies of the reprogramming of stromal cells and cancer cells. In CAF-derived exosomes, LINC01614 inhibited LUAD growth and reprogrammed glutamine addiction in tumor cells by activating NF-κB to upregulate the expression of the glutamine transporters SLC38A2 and SLC7A5 [79]. In addition, other studies have indicated that CAFs regulate glutaminolysis in CRC and prostate cancer via distinct pathways, such as glutamine synthetase in CRC and Ras, which activates micropinocytosis, in prostate cancer [80, 81]. Additionally, in pancreatic cancer, stromal cells have been shown to regulate glutamine metabolic reprogramming in PDAC cells through the TGF-β/SMAD5 axis, which targets BCAT1, SDF-1a and IL-6 secretion activated by Nrf-2 respectively [82, 83].
However, resistance to glutamine deprivation in stromal cells has been demonstrated by p62-mediated polyubiquitination via upregulated ATF4 expression [84]. In addition, the glutamine metabolism has been shown to be reprogrammed by CAFs through the secretion of miR-105 from cancer cells, promoting tumor growth and metastasis in many solid cancers [68, 85] (Fig. 4).
Lipid metabolism reprogramming
Previous studies have rarely investigated the lipid metabolism of CAFs; however, recent studies have focused on the principal role of lipid metabolism reprogramming in tumorigenesis, metastasis and potential therapeutic targets [62, 64, 86].
With respect to lipid metabolism, most studies have focused on how lipid metabolic reprogramming affects CAFs. HSP111 reprograms the metabolism of CAFs and promotes CRLM by phosphorylating ACLY to increase H3K27 acetylation and the expression of components of the CXCL5-CXCR2 axis [87]. Additionally, in CRC, iCAFs are correlated with lipid metabolism, and FASN in CAFs promotes tumor migration by lipid metabolism reprogramming [16, 88]. In prostate cancer, the reprogramming of lipid metabolism and amplification of MTOCs have been shown to increase CAF plasticity [89].
However, few studies have investigated lipid metabolism in stromal cells and tumor cells. TNBC-derived CAFs can reprogram monocytes into lipid-associated macrophage (LAMs) via the CXCL12-CXCR4 axis, suppressing immune response such as T cell activation [90] (Fig. 4).
CAFs with metastasis
CAFs are the major stromal cells in tumor tissue, and their crosstalk with TAMs, TANs, epithelial cells and cancer cells regulates tumorigenesis, invasion, drug resistance and metastasis [91]. Next, we summarize studies of the association between CAFs and metastasis in different cancer types.
Gastric cancer
Secreting numerous cytokines in the TME, CAFs remodel the tumor stroma in gastric cancer, supporting tumor progression, angiogenesis and metastasis. Herein, we summarize recent studies on tumor cell metastasis and lymph node metastasis.
TNC and twist1 are regulators of many malignant tumors, such as ESCC and CRC, and a recent study revealed that their expression was related to lymph node metastasis in gastric cancer patients [92, 93]. Yang et al. also demonstrated that the expression of KLF5 was associated with lymph node metastasis via activation of the CCL5/CCR5 axis [92]. In addition, other studies have indicated that lymph node metastasis in gastric cancer is associated with the expression of CD9 and the downregulation of FGF9 expression in CAFs [94, 95].
Recently, CAFs were shown to promote the metastasis of gastric cancer via the TNF-α/IL-33/ST2L signaling pathway and the CAF-derived HGF and IL-11/MUC1 signaling pathways [96,97,98]. However, another study indicated that exo-miR-139 derived from CAFs inhibited the tumor progression and metastasis of gastric cancer by decreasing MMP11 expression, indicating that CAFs have bidirectional functions [99] (Fig. 5).
Colorectal cancer
Colorectal cancer (CRC) is the world’s most lethal cancer worldwide, and colorectal metastasis (CRLM) is one of the awkward problems in CRC therapy.
A disintegrin and metalloproteinase (ADAM) and endoglin are two different factors expressed in CAFs that promote CRLM via ADAM10 levels in serum and endoglin-BMP9 axis signaling [100, 101]. In addition, the crosstalk between cancer cells and CAFs via TRAIL-BMP2 has been shown to maintain a feedback loop in a CRLM mouse model [102]. This crosstalk could lead to the development of promising treatments or serve as a predictor of CRC metastasis. The expression of exo-miR-92a-3p is related to CRLM through regulating downstream FBXW7 and MOAP1 expression in CAFs [103].
However, Ruixiao Li et al. have demonstrated that Jianpi Jiedu Recipe (JPJDR) could reduce CRLM through ITGBL1/TNFAIP3/ NF-κB signaling in CAFs [104] (Fig. 5).
Lung cancer
Lung metastasis is one of the main causes of lung cancer-related deaths worldwide, and lung cancer metastasis is also a key problem in tumor therapy and tumor relapse.
Regulated by miR-1247-3p, CAFs have been shown to induce CCL5 expression through the activation of the HIF1α/ZEB1 axis and the β1 integrin/NF-κB axis to promote lung metastasis in HCC [105, 106]. In addition, researchers have demonstrated that the TGF-β1/HOTAIR signaling pathway and the integrin α2β1/TGF-β axis were promote lung metastasis in patients with breast cancer and salivary adenoid cystic carcinoma, respectively [107, 108].
Other studies have demonstrated that several biomarkers and cytokines derived from CAFs, such as vimentin, FAPα, and HMGB1, are positively related to lung tumor metastasis [109,110,111]. However, Bin Xue et al. demonstrated that miR-200 expression is associated with lung cancer prognosis and metastasis via the induction of Notch activation in CAFs [112] (Fig. 5).
Breast cancer
As one of the most common malignant cancers in women, breast cancer is more common than lung cancer, colorectal cancer and thyroid carcinoma. Herein, we have summarize studies that address the promotion and inhibition of metastasis signaling in breast cancer.
Both the NLRP3/IL-1β axis and DDR2 have been shown to contribute to the cancer metastasis in CAFs in vivo and are promising therapeutic targets [113, 114]. In addition, exosomal miRNAs derived from CAFs, such as miR-500a-5p, miR-18b and miR-222, promote metastasis whereas miR-16 and miR-148a expression suppresses metastasis [115,116,117,118]. Other studies have revealed that the TGF-β1/HOTAIR and IL-3/integrin β3-p38 MAPK axes promote tumor metastasis [108, 119].
However, CAFs have bidirectional characteristics, i.e., promote tumorigenesis and inhibit tumor metastasis. Research has shown that p85α expression suppresses tumor metastasis via Wnt10b signaling, and that CCM3 secretion reduces metastasis through YAP/TAZ signaling [120, 121] (Fig. 5).
CAFs with drug resistance
Increasing evidence has shown that CAFs play a key role in drug resistance through signal transduction pathways, drug delivery and acceptance systems, and DNA damage repair. Drug resistance induced by CAFs can be found in many kinds of solid tumors, such as breast cancer, pancreatic cancer, and lung cancer. However, we will address how CAFs promote tumorigenesis through TGF, IL-6, CCL, PAI, NRG1 and some exosomes and inhibit tumorigenesis through CCL, TPL, Nav and GDC0449 [122,123,124,125].
Promoting tumorigenesis
As the bridge between growth factors and their corresponding receptors, TGFβ plays an important role in signaling pathways, e.g., the FOXO1/TGFβ1 signaling loop, IL1b/TGFβ-mediated crosstalk, the TGFβ1/SMAD3 signaling pathway, the TGF-β1/PI3K/AKT/mTOR pathway, and TGFβ accumulation [126,127,128,129,130]. In resistance to oxaliplatin, TGFβ signal transduction, an IL-1β antibody and a TGFBR1 inhibitor can drive TAK-mediated activation to decrease the JAK/STAT and PI3KCA/AKT pathways in CRC [127]. Furthermore, TGFβ1/SMAD3 activation, a fibrotic phenotype and nintedanib resistance were shown to be more strongly related to ADC than to SCC in lung carcinoma [128]. Moreover, in NSCLC, crosstalk activates the PI3K/AKT/mTOR pathway to induce the MDR by releasing TGF-β [129]. In another chemoresistance mechanism, the crosstalk between the tumor cells and CAFs promotes the activation and expression of FOXO1, which leads to TGFβ1 expression through autocrine/paracrine loops in ESCC. However, Yamei Chen et al. recently reported that ANXA1/FPR2 signaling could counteract the function of TGFβ in ESCC [123]. Recent research revealed TGFβ-myCAF signaling could be modulated by the EMILIN1 gene in IFNγ-iCAFs in breast cancer [125].
Many studies have demonstrated that IL-6-specific functions in CAFs involve the IL-6/CXCR7 axis and the IL-6/Jak1/STAT3 axis, which play roles in the immune response, EMT and cancer cell migration [131,132,133,134]. For DNA repair in ESCC, CXCR7 expression is increased by IL6 to protect cells from apoptosis via the activator of transcription 3/NF-κB pathway [131]. In addition, the monoclonal anti-IL-6R antibody tocilizumab increases apoptosis in cancer cells through the IL-6/Jak1/STAT3 axis, promoting tumorigenesis, invasion and antiapoptotic proteins expression in gastric cancer [132]. According to a recent study, in gastric cancer, in combination with M2 macrophages, eCAFs promote tumor invasion and decrease survival through the expression of periostin [122]. Because of anti-PD-L1 resistance in hepatocellular carcinoma, CAFs expressing high levels of IL-6 support the disruption of tumor-infiltrating T-cell function, resulting in the generation of immunosuppressive cells in the TME [133].
5-Fluorouracil and paclitaxel resistance can be induced by Snail-overexpressing fibroblasts, which secrete CCL1 via the TGFβ/NF-κB signaling pathway [135]. PAI-1, which is produced by inflammatory cells and CAFs, is involved in resistance in various tumor tissues. Research has demonstrated that AKT and ERK1/2 signaling is activated by PAI-1 and impedes the accumulation of ROS and caspase-3 activity during cisplatin resistance in ESCC [136] (Fig. 3). In addition, PAI-1 increases the expression of α-SMA, which is expressed in MFs, and reduces chemoresistance in lung cancer [137]. Recent studies have supported the resistance to antiandrogens in the EGFR/ERK pathway through miR-146a-5p and the NRG1/HER3 axis in prostate cancer; however, obstructing NRG1/HER3 and inhibiting migration and growth strengthens ADCC in NRG1-positive pancreatic tumors and CAFs [138, 139]. In addition, studies have shown that in pancreatic cancer, the SDF-1/CXCR4/SATB-1 axis induces tumor progression and GEM resistance by building a positive feedback loop [140].
For pancreatic cancer, the inhibitor of exosome release GW4869 suppresses epithelial cell proliferation and GEM resistance, as exosomes increase Snail expression, and Snail expression is correlated with the promotion of drug resistance in lung cancer [141, 142]. In addition, miR-106b, which targets to TP53INP1 and increases GEM resistance in pancreatic cancer, is released by exosomes from CAFs to tumor cells [143]. Another study reported that CAFs secrete exosomes decorated with miRNA-130a via PUM2 and inhibit apoptosis via the PKM2/BCL2 axis to promote cisplatin resistance in NSCLC [70, 144]. In CRC, exosomal miR-181d-5p, the direct target of NCALD, is affected by METTL3 via DGCR8 in CAFs, whereas the sensitivity of CRC to 5FU is affected by NCALD [145]. Recently, Arthur Dondi et al. revealed that lung cancer metastasis occurs through miR-1290/MT1G/AKT signaling in NFs [146].
Inhibiting tumorigenesis
Recently, an increasing number of nanoparticle technologies that enhance therapeutic efficacy, inhibit signaling pathways, and reduce toxic side effects, have been developed for cancer treatment [147,148,149,150]. In gastric cancer, PSN38@TPL-Nsa nanoparticles have been shown to inhibit tumor progression, and improve antimetastatic efficacy because TPL is a suitable stromal reprogramming inducer [147]. In addition, nano-doxorubicin has been shown to improve drug efficacy and reduce cardiotoxicity in pancreatic cancer patients [150]. CCL plays crucial roles in chemoresistance, such as 5-fluorouracil resistance, paclitaxel resistance, and cisplatin resistance, in CRC, HNSCC, ovarian cancer and melanoma [151,152,153]. In addition, cisplatin resistance in ovarian cancer and HNSCC has been shown to occur via the regulation of the STAT3 and PI3K/Akt signaling pathways as well as sensitization effects of CAFs, respectively [151, 153] (Fig. 2). In addition, a recent study reported that EMT was increased by miR-146a-5p through the modulation castration resistance via the EGFR/ERK pathway [154] (Table 1).
Conclusion
To date, many studies have focused on components of the TME, such as CAFs, the ECM, and TAMs, rather than on tumor cells. Herein, we summarized the most recent studies regarding CAF-targeting therapy. Recently, we revealed cross-talk among miscellaneous cells and the spatial landscape in CRC, PDAC, BC. These findings have significant implications for comprehensively understanding the crosstalk between CAFs and cancer cells, the macroscopic spatial structure of CAFs and therapeutic targets in tumor tissue. Drug resistance, angiogenesis, metabolic reprogramming and tumor metastasis are four hallmarks of cancer. Findings thus far have identified promising therapeutic targets that should be developed in future studies. Taken together, more studies involving single-cell spatial transcriptomics sequencing should be conducted to obtain further knowledge of tumor progression, metastasis, drug resistance, angiogenesis, and metabolic reprogramming.
Data availability
No datasets were generated or analysed during the current study.
Abbreviations
- CAF:
-
Cancer associated fibroblast
- TILs:
-
Tumor infiltrating lymphocytes
- TIDCs:
-
Tumor infiltrating dendritic cells
- TAMs:
-
Tumor associated macrophages
- TANs:
-
Tumor associated neutrophils
- MDSCs:
-
Myeloid derived suppressor cells
- ST:
-
Spatial transcriptomics
- DSP:
-
Digital spatial profiling
- PDAC:
-
Pancreatic ductal adenocarcinoma
- GSEA:
-
Gene set enrichment analysis
- NL cell:
-
Natural killer cell
- MMP:
-
Matrix metalloproteinase
- GPNMB:
-
Glycoprotein nonmetastatic B
- TME:
-
Tumor microenvironment
- TGF:
-
Transforming growth factor
- IL:
-
Interleukin
- CCL:
-
C-C motif chemokine ligand
- PAI:
-
Plasminogen activator inhibitor
- NRG:
-
Neuregulin
- TPL:
-
Triptolide
- FOXO:
-
Forkhead box protein
- SMAD:
-
The Caenorhabditis elegans SMA and MAD family
- PI3K:
-
Phosphoinositide 3-kinases
- mTOR:
-
the mammalian target of rapamycin
- AKT:
-
Protein kinase B
- ADC:
-
Lung adenocarcinoma
- SCC:
-
Lung squamous cell carcinoma
- MDR:
-
MultiDrug Resistance
- ESCC:
-
Esophageal squamous-cell carcinoma
- CXCR7:
-
C-X-C Motif Chemokine Receptor 7
- JAK1:
-
Janus kinase 1
- STAT:
-
Signal Transducer and Activator of Transcription
- NF-κB:
-
Nuclear Factor kappa B
- ROS:
-
Reactive oxygen species
- EGFR:
-
Epidermal growth factor receptor
- ERK:
-
Extracellular-regulated kinase
- HER3:
-
Human epidermal growth factor receptor 3
- SDF-1:
-
Stromal cell-derived factor-1
- SATB-1:
-
Special AT-rich binding protein
- GEM:
-
Gemcitabine
- TP53INP1:
-
Tumor protein 53-induced nuclear protein 1
- PUM2:
-
PUMILIO2
- PKM2:
-
The M2 isoform of pyruvate kinase
- BCL2:
-
B-cell lymphoma-2
- NSCLC:
-
Non-small-cell lung cancer
- CRC:
-
Colorectal cancer
- NCALD:
-
Neurocalcinδ
- METTL3:
-
N6‑methyladenosine (m6A) methyltransferase like 3
- DGCR8:
-
DiGeorge Syndrome Critical Region 8
- 5-FU:
-
5-Fluorouracil
- PSN38@TPL-nsa:
-
SN38 prodrug polymeric micelles@ triptolide-naphthalene sulfonamide
- EMT:
-
Epithelial–mesenchymal transition
- ECM:
-
Extracellular matrix
- TNBC:
-
Triple-negative subtype of breast cancer
- FGF:
-
Fibroblast growth factor
- VEGF:
-
Vascular endothelial growth factor
- HGF:
-
Hepatocyte growth factor
- HUVEC:
-
Human umbilical vein endothelial cells
- MSC:
-
Mesenchymal stem cells
- MMP:
-
Matrix metalloproteinases
- EPA:
-
Eicosapentaenoic acid
- ATF4:
-
Activating transcription factor 4
- sEV:
-
Small extracellular vesicles
- ITGB4:
-
Integrin beta 4
- GFPT2:
-
Glutamine-fructose-6-phosphate transaminase 2
- MAPK:
-
Mitogen-activated protein kinases
- PFKFB3:
-
6-phosphofructo-2-kinase/fructose-2,6biphosphatase 3
- CAV1:
-
Caveolin1
- MCT:
-
Monocarboxylate transporter
- LPA:
-
Lysophosphatidic acid
- HIF 1α:
-
Hypoxia inducible factor 1α
- LDHA:
-
Lactate dehydrogenase A
- ASPN:
-
Asporin
- LUAD:
-
Lung adenocarcinoma
- SDF-1:
-
Stromal-derived factor-1
- CRLM:
-
Colorectal liver metastases
- ACLY:
-
ATP-citrate lyase
- MTOC:
-
Microtubule-organizing centers
- ADAM:
-
A disintegrin and metalloproteinase
- TRAIL:
-
TNF-related apoptosis-inducing ligand
- BMP:
-
Bone morphogenetic proteins
- ITGBL 1:
-
Integrin beta- like 1
- JPJDR:
-
Jianpi Jiedu Recipe
- TNFAIP3:
-
TNF alpha-induced protein 3
- ZEB1:
-
Zinc finger enhancer-binding protein 1
- HOTAIR:
-
HOX transcript antisense RNA
- HMGB1:
-
High mobility group box 1
References
Ishii G, Ochiai A, Neri S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliv Rev. 2016;99(Pt B):186–96.
Nascimento C, Ferreira F. Tumor microenvironment of human breast cancer, and feline mammary carcinoma as a potential study model. Biochim et Biophys acta Reviews cancer. 2021;1876(1):188587.
Huang H, Brekken RA. Recent advances in understanding cancer-associated fibroblasts in pancreatic cancer. Am J Physiol Cell Physiol. 2020;319(2):C233–43.
Biffi G, Tuveson DA. Diversity and Biology of Cancer-Associated fibroblasts. Physiol Rev. 2021;101(1):147–76.
Vicent S, Sayles LC, Vaka D, Khatri P, Gevaert O, Chen R, et al. Cross-species functional analysis of cancer-associated fibroblasts identifies a critical role for CLCF1 and IL-6 in non-small cell lung cancer in vivo. Cancer Res. 2012;72(22):5744–56.
Rimal R, Desai P, Daware R, Hosseinnejad A, Prakash J, Lammers T, et al. Cancer-associated fibroblasts: origin, function, imaging, and therapeutic targeting. Adv Drug Deliv Rev. 2022;189:114504.
Zhuravlev F. Theranostic Radiopharmaceuticals Targeting Cancer-Associated fibroblasts. Curr Radiopharmaceuticals. 2021;14(4):374–93.
Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 2021;20(1):131.
Marx V. Method of the year: spatially resolved transcriptomics. Nat Methods. 2021;18(1):9–14.
Jovic D, Liang X, Zeng H, Lin L, Xu F, Luo Y. Single-cell RNA sequencing technologies and applications: a brief overview. Clin Translational Med. 2022;12(3):e694.
Moses L, Pachter L. Museum of spatial transcriptomics. Nat Methods. 2022;19(5):534–46.
Guo W, Zhou B, Yang Z, Liu X, Huai Q, Guo L, et al. Integrating microarray-based spatial transcriptomics and single-cell RNA-sequencing reveals tissue architecture in esophageal squamous cell carcinoma. EBioMedicine. 2022;84:104281.
Shi ZD, Sun Z, Zhu ZB, Liu X, Chen JZ, Hao L, et al. Integrated single-cell and spatial transcriptomic profiling reveals higher intratumour heterogeneity and epithelial-fibroblast interactions in recurrent bladder cancer. Clin Translational Med. 2023;13(7):e1338.
Mah CK, Ahmed N, Lam D, Monell A, Kern C, Han Y et al. Bento: a toolkit for subcellular analysis of spatial transcriptomics data. bioRxiv. 2022.
Hwang WL, Jagadeesh KA, Guo JA, Hoffman HI, Yadollahpour P, Reeves JW, et al. Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment. Nat Genet. 2022;54(8):1178–91.
Peng Z, Ye M, Ding H, Feng Z, Hu K. Spatial transcriptomics atlas reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment components in colorectal cancer. J Translational Med. 2022;20(1):302.
Makutani Y, Kawakami H, Tsujikawa T, Yoshimura K, Chiba Y, Ito A, et al. Contribution of MMP14-expressing cancer-associated fibroblasts in the tumor immune microenvironment to progression of colorectal cancer. Front Oncol. 2022;12:956270.
Truong DD, Kratz A, Park JG, Barrientos ES, Saini H, Nguyen T, et al. A human organotypic microfluidic tumor model permits investigation of the interplay between patient-derived fibroblasts and breast Cancer cells. Cancer Res. 2019;79(12):3139–51.
Ma C, Yang C, Peng A, Sun T, Ji X, Mi J, et al. Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment. Mol Cancer. 2023;22(1):170.
Ferri-Borgogno S, Zhu Y, Sheng J, Burks JK, Gomez JA, Wong KK, et al. Spatial transcriptomics depict ligand-receptor cross-talk heterogeneity at the Tumor-Stroma Interface in Long-Term Ovarian Cancer survivors. Cancer Res. 2023;83(9):1503–16.
Ren X, Kang B, Zhang Z. Understanding tumor ecosystems by single-cell sequencing: promises and limitations. Genome Biol. 2018;19(1):211.
Henon C, Vibert J, Eychenne T, Gruel N, Colmet-Daage L, Ngo C, et al. Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in DSRCTs. Cell Rep Med. 2024;5(6):101582.
Asleh K, Riaz N, Nielsen TO. Heterogeneity of triple negative breast cancer: current advances in subtyping and treatment implications. J Exp Clin Cancer Res. 2022;41(1):265.
Fan J, Lu F, Qin T, Peng W, Zhuang X, Li Y, et al. Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance. Nat Genet. 2023;55(12):2175–88.
Sun C, Li T, Song X, Huang L, Zang Q, Xu J, et al. Spatially resolved metabolomics to discover tumor-associated metabolic alterations. Proc Natl Acad Sci USA. 2019;116(1):52–7.
Zhou PY, Zhou C, Gan W, Tang Z, Sun BY, Huang JL, et al. Single-cell and spatial architecture of primary liver cancer. Commun Biology. 2023;6(1):1181.
Zhang G, Ji P, Xia P, Song H, Guo Z, Hu X, et al. Identification and targeting of cancer-associated fibroblast signature genes for prognosis and therapy in cutaneous melanoma. Comput Biol Med. 2023;167:107597.
Lee J, Hyeon DY, Hwang D. Single-cell multiomics: technologies and data analysis methods. Exp Mol Med. 2020;52(9):1428–42.
Yu X, Liu R, Gao W, Wang X, Zhang Y. Single-cell omics traces the heterogeneity of prostate cancer cells and the tumor microenvironment. Cell Mol Biol Lett. 2023;28(1):38.
Dzobo K, Dandara C. Architecture of Cancer-Associated fibroblasts in Tumor Microenvironment: Mapping their origins, heterogeneity, and role in Cancer Therapy Resistance. OMICS. 2020;24(6):314–39.
De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017;17(8):457–74.
Liubomirski Y, Lerrer S, Meshel T, Rubinstein-Achiasaf L, Morein D, Wiemann S, et al. Tumor-stroma-inflammation networks promote pro-metastatic chemokines and aggressiveness characteristics in Triple-negative breast Cancer. Front Immunol. 2019;10:757.
Pausch TM, Aue E, Wirsik NM, Freire Valls A, Shen Y, Radhakrishnan P, et al. Metastasis-associated fibroblasts promote angiogenesis in metastasized pancreatic cancer via the CXCL8 and the CCL2 axes. Sci Rep. 2020;10(1):5420.
Arena S, Salati M, Sorgentoni G, Barbisan F, Orciani M. Characterization of tumor-derived mesenchymal stem cells potentially differentiating into cancer-associated fibroblasts in lung cancer. Clin Translational Oncology: Official Publication Federation Span Oncol Soc Natl Cancer Inst Mexico. 2018;20(12):1582–91.
Lang J, Zhao X, Qi Y, Zhang Y, Han X, Ding Y, et al. Reshaping prostate Tumor Microenvironment to suppress Metastasis via Cancer-Associated Fibroblast inactivation with Peptide-Assembly-Based Nanosystem. ACS Nano. 2019;13(11):12357–71.
Sorrentino C, Miele L, Porta A, Pinto A, Morello S. Activation of the A2B adenosine receptor in B16 melanomas induces CXCL12 expression in FAP-positive tumor stromal cells, enhancing tumor progression. Oncotarget. 2016;7(39):64274–88.
Augsten M, Hägglöf C, Olsson E, Stolz C, Tsagozis P, Levchenko T, et al. CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth. Proc Natl Acad Sci USA. 2009;106(9):3414–9.
Nakamura Y. Multiple therapeutic applications of RBM-007, an Anti-FGF2 aptamer. Cells. 2021;10(7).
Marques P, Barry S, Carlsen E, Collier D, Ronaldson A, Awad S, et al. Pituitary tumour fibroblast-derived cytokines influence tumour aggressiveness. Endocrine-related Cancer. 2019;26(12):853–65.
Ben Baruch B, Mantsur E, Franco-Barraza J, Blacher E, Cukierman E, Stein R. CD38 in cancer-associated fibroblasts promotes pro-tumoral activity. Lab Invest. 2020;100(12):1517–31.
Eiro N, González L, Martínez-Ordoñez A, Fernandez-Garcia B, González LO, Cid S, et al. Cancer-associated fibroblasts affect breast cancer cell gene expression, invasion and angiogenesis. Cell Oncol (Dordrecht). 2018;41(4):369–78.
Zhou X, Yan T, Huang C, Xu Z, Wang L, Jiang E, et al. Melanoma cell-secreted exosomal mir-155-5p induce proangiogenic switch of cancer-associated fibroblasts via SOCS1/JAK2/STAT3 signaling pathway. J Exp Clin Cancer Res. 2018;37(1):242.
Najafi M, Farhood B, Mortezaee K. Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J Cell Biochem. 2019;120(3):2782–90.
Limoge M, Safina A, Beattie A, Kapus L, Truskinovsky AM, Bakin AV. Tumor-fibroblast interactions stimulate tumor vascularization by enhancing cytokine-driven production of MMP9 by tumor cells. Oncotarget. 2017;8(22):35592–608.
Lin NN, Wang P, Zhao D, Zhang FJ, Yang K, Chen R. Significance of oral cancer-associated fibroblasts in angiogenesis, lymphangiogenesis, and tumor invasion in oral squamous cell carcinoma. J oral Pathol Medicine: Official Publication Int Association Oral Pathologists Am Acad Oral Pathol. 2017;46(1):21–30.
Unterleuthner D, Neuhold P, Schwarz K, Janker L, Neuditschko B, Nivarthi H, et al. Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer. Angiogenesis. 2020;23(2):159–77.
Al-Harbi B, Aboussekhra A. Cucurbitacin I (JSI-124)-dependent inhibition of STAT3 permanently suppresses the pro-carcinogenic effects of active breast cancer-associated fibroblasts. Mol Carcinog. 2021;60(4):242–51.
Cohen N, Shani O, Raz Y, Sharon Y, Hoffman D, Abramovitz L, et al. Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of chitinase 3-like 1. Oncogene. 2017;36(31):4457–68.
Pape J, Magdeldin T, Stamati K, Nyga A, Loizidou M, Emberton M, et al. Cancer-associated fibroblasts mediate cancer progression and remodel the tumouroid stroma. Br J Cancer. 2020;123(7):1178–90.
Salvatore V, Teti G, Focaroli S, Mazzotti MC, Mazzotti A, Falconi M. The tumor microenvironment promotes cancer progression and cell migration. Oncotarget. 2017;8(6):9608–16.
Fan J, Xu G, Chang Z, Zhu L, Yao J. miR-210 transferred by lung cancer cell-derived exosomes may act as proangiogenic factor in cancer-associated fibroblasts by modulating JAK2/STAT3 pathway. Clinical science (London, England: 1979). 2020;134(7):807 – 25.
Watanabe K, Shiga K, Maeda A, Harata S, Yanagita T, Suzuki T et al. Chitinase 3-like 1 secreted from cancer-associated fibroblasts promotes tumor angiogenesis via interleukin-8 secretion in colorectal cancer. Int J Oncol. 2022;60(1).
Hayashi Y, Tsujii M, Kodama T, Akasaka T, Kondo J, Hikita H, et al. p53 functional deficiency in human colon cancer cells promotes fibroblast-mediated angiogenesis and tumor growth. Carcinogenesis. 2016;37(10):972–84.
Ando N, Hara M, Shiga K, Yanagita T, Takasu K, Nakai N, et al. Eicosapentaenoic acid suppresses angiogenesis via reducing secretion of IL–6 and VEGF from colon cancer–associated fibroblasts. Oncol Rep. 2019;42(1):339–49.
Li J, Liu X, Zang S, Zhou J, Zhang F, Sun B, et al. Small extracellular vesicle-bound vascular endothelial growth factor secreted by carcinoma-associated fibroblasts promotes angiogenesis in a bevacizumab-resistant manner. Cancer Lett. 2020;492:71–83.
Shen H, Yu X, Yang F, Zhang Z, Shen J, Sun J, et al. Reprogramming of normal fibroblasts into Cancer-Associated fibroblasts by miRNAs-Mediated CCL2/VEGFA signaling. PLoS Genet. 2016;12(8):e1006244.
Kobayashi H, Enomoto A, Woods SL, Burt AD, Takahashi M, Worthley DL. Cancer-associated fibroblasts in gastrointestinal cancer. Nat Reviews Gastroenterol Hepatol. 2019;16(5):282–95.
Verginadis II, Avgousti H, Monslow J, Skoufos G, Chinga F, Kim K, et al. A stromal Integrated stress response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression. Nat Cell Biol. 2022;24(6):940–53.
Sharma M, Turaga RC, Yuan Y, Satyanarayana G, Mishra F, Bian Z et al. Simultaneously targeting cancer-associated fibroblasts and angiogenic vessel as a treatment for TNBC. J Exp Med. 2021;218(4).
Vasiukov G, Novitskaya T, Zijlstra A, Owens P, Ye F, Zhao Z, et al. Myeloid cell-derived TGFβ signaling regulates ECM deposition in Mammary Carcinoma via Adenosine-Dependent mechanisms. Cancer Res. 2020;80(12):2628–38.
Zonneville J, Safina A, Truskinovsky AM, Arteaga CL, Bakin AV. TGF-β signaling promotes tumor vasculature by enhancing the pericyte-endothelium association. BMC Cancer. 2018;18(1):670.
Li Z, Sun C, Qin Z. Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming. Theranostics. 2021;11(17):8322–36.
Wu D, Zhuo L, Wang X. Metabolic reprogramming of carcinoma-associated fibroblasts and its impact on metabolic heterogeneity of tumors. Semin Cell Dev Biol. 2017;64:125–31.
Zhu Y, Li X, Wang L, Hong X, Yang J. Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment. Front Endocrinol. 2022;13:988295.
Brown TP, Ganapathy V. Lactate/GPR81 signaling and proton motive force in cancer: role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther. 2020;206:107451.
Sung JS, Kang CW, Kang S, Jang Y, Chae YC, Kim BG, et al. ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts. Oncogene. 2020;39(3):664–76.
Becker LM, O’Connell JT, Vo AP, Cain MP, Tampe D, Bizarro L, et al. Epigenetic reprogramming of Cancer-Associated fibroblasts deregulates glucose metabolism and facilitates progression of breast Cancer. Cell Rep. 2020;31(9):107701.
Yan W, Wu X, Zhou W, Fong MY, Cao M, Liu J, et al. Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nat Cell Biol. 2018;20(5):597–609.
Cruz-Bermúdez A, Laza-Briviesca R, Vicente-Blanco RJ, García-Grande A, Coronado MJ, Laine-Menéndez S, et al. Cancer-associated fibroblasts modify lung cancer metabolism involving ROS and TGF-β signaling. Free Radic Biol Med. 2019;130:163–73.
Wang D, Zhao C, Xu F, Zhang A, Jin M, Zhang K, et al. Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2. Theranostics. 2021;11(6):2860–75.
Zhang W, Bouchard G, Yu A, Shafiq M, Jamali M, Shrager JB, et al. GFPT2-Expressing Cancer-Associated fibroblasts mediate metabolic reprogramming in human lung adenocarcinoma. Cancer Res. 2018;78(13):3445–57.
Yang J, Shi X, Yang M, Luo J, Gao Q, Wang X, et al. Glycolysis reprogramming in cancer-associated fibroblasts promotes the growth of oral cancer through the lncRNA H19/miR-675-5p/PFKFB3 signaling pathway. Int J Oral Sci. 2021;13(1):12.
Jiang E, Xu Z, Wang M, Yan T, Huang C, Zhou X, et al. Tumoral microvesicle-activated glycometabolic reprogramming in fibroblasts promotes the progression of oral squamous cell carcinoma. FASEB Journal: Official Publication Federation Am Soc Experimental Biology. 2019;33(4):5690–703.
Eisenberg L, Eisenberg-Bord M, Eisenberg-Lerner A, Sagi-Eisenberg R. Metabolic alterations in the tumor microenvironment and their role in oncogenesis. Cancer Lett. 2020;484:65–71.
Radhakrishnan R, Ha JH, Jayaraman M, Liu J, Moxley KM, Isidoro C, et al. Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts. Cancer Lett. 2019;442:464–74.
Sasaki Y, Takagane K, Konno T, Itoh G, Kuriyama S, Yanagihara K, et al. Expression of asporin reprograms cancer cells to acquire resistance to oxidative stress. Cancer Sci. 2021;112(3):1251–61.
Zhang Z, Gao Z, Rajthala S, Sapkota D, Dongre H, Parajuli H, et al. Metabolic reprogramming of normal oral fibroblasts correlated with increased glycolytic metabolism of oral squamous cell carcinoma and precedes their activation into carcinoma associated fibroblasts. Cell Mol Life Sci. 2020;77(6):1115–33.
Vettore L, Westbrook RL, Tennant DA. New aspects of amino acid metabolism in cancer. Br J Cancer. 2020;122(2):150–6.
Liu T, Han C, Fang P, Ma Z, Wang X, Chen H, et al. Cancer-associated fibroblast-specific lncRNA LINC01614 enhances glutamine uptake in lung adenocarcinoma. J Hematol Oncol. 2022;15(1):141.
Wang J, Delfarah A, Gelbach PE, Fong E, Macklin P, Mumenthaler SM, et al. Elucidating tumor-stromal metabolic crosstalk in colorectal cancer through integration of constraint-based models and LC-MS metabolomics. Metab Eng. 2022;69:175–87.
Mishra R, Haldar S, Suchanti S, Bhowmick NA. Epigenetic changes in fibroblasts drive cancer metabolism and differentiation. Endocrine-related Cancer. 2019;26(12):R673–88.
Wu YS, Looi CY, Subramaniam KS, Masamune A, Chung I. Soluble factors from stellate cells induce pancreatic cancer cell proliferation via Nrf2-activated metabolic reprogramming and ROS detoxification. Oncotarget. 2016;7(24):36719–32.
Zhu Z, Achreja A, Meurs N, Animasahun O, Owen S, Mittal A, et al. Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours. Nat Metabolism. 2020;2(8):775–92.
Linares JF, Cordes T, Duran A, Reina-Campos M, Valencia T, Ahn CS, et al. ATF4-Induced Metabolic Reprograming is a synthetic vulnerability of the p62-Deficient tumor stroma. Cell Metab. 2017;26(6):817–e296.
Yang L, Achreja A, Yeung TL, Mangala LS, Jiang D, Han C, et al. Targeting stromal glutamine synthetase in Tumors disrupts Tumor Microenvironment-Regulated Cancer Cell Growth. Cell Metab. 2016;24(5):685–700.
Koundouros N, Poulogiannis G. Reprogramming of fatty acid metabolism in cancer. Br J Cancer. 2020;122(1):4–22.
Zhang C, Wang XY, Zhang P, He TC, Han JH, Zhang R, et al. Cancer-derived exosomal HSPC111 promotes colorectal cancer liver metastasis by reprogramming lipid metabolism in cancer-associated fibroblasts. Cell Death Dis. 2022;13(1):57.
Gong J, Lin Y, Zhang H, Liu C, Cheng Z, Yang X, et al. Reprogramming of lipid metabolism in cancer-associated fibroblasts potentiates migration of colorectal cancer cells. Cell Death Dis. 2020;11(4):267.
Nardi F, Fitchev P, Franco OE, Ivanisevic J, Scheibler A, Hayward SW et al. PEDF regulates plasticity of a novel lipid-MTOC axis in prostate cancer-associated fibroblasts. J Cell Sci. 2018;131(13).
Timperi E, Gueguen P, Molgora M, Magagna I, Kieffer Y, Lopez-Lastra S, et al. Lipid-Associated macrophages Are Induced by Cancer-Associated fibroblasts and mediate Immune suppression in breast Cancer. Cancer Res. 2022;82(18):3291–306.
Hill BS, Sarnella A, D’Avino G, Zannetti A. Recruitment of stromal cells into tumour microenvironment promote the metastatic spread of breast cancer. Sem Cancer Biol. 2020;60:202–13.
Yang T, Chen M, Yang X, Zhang X, Zhang Z, Sun Y, et al. Down-regulation of KLF5 in cancer-associated fibroblasts inhibit gastric cancer cells progression by CCL5/CCR5 axis. Cancer Biol Ther. 2017;18(10):806–15.
Qi W, Yang Z, Li H, Cui Y, Xuan Y. The role of Tenascin-C and Twist1 in gastric cancer: cancer progression and prognosis. APMIS: acta pathologica, microbiologica, et immunologica Scandinavica. 2019;127(2):64–71.
Wang R, Sun Y, Yu W, Yan Y, Qiao M, Jiang R, et al. Downregulation of miRNA-214 in cancer-associated fibroblasts contributes to migration and invasion of gastric cancer cells through targeting FGF9 and inducing EMT. J Exp Clin Cancer Res. 2019;38(1):20.
Miki Y, Yashiro M, Okuno T, Kitayama K, Masuda G, Hirakawa K, et al. CD9-positive exosomes from cancer-associated fibroblasts stimulate the migration ability of scirrhous-type gastric cancer cells. Br J Cancer. 2018;118(6):867–77.
Zhou Q, Wu X, Wang X, Yu Z, Pan T, Li Z, et al. The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis. Oncogene. 2020;39(7):1414–28.
Ding X, Ji J, Jiang J, Cai Q, Wang C, Shi M, et al. HGF-mediated crosstalk between cancer-associated fibroblasts and MET-unamplified gastric cancer cells activates coordinated tumorigenesis and metastasis. Cell Death Dis. 2018;9(9):867.
Wang X, Che X, Liu C, Fan Y, Bai M, Hou K, et al. Cancer-associated fibroblasts-stimulated interleukin-11 promotes metastasis of gastric cancer cells mediated by upregulation of MUC1. Exp Cell Res. 2018;368(2):184–93.
Xu G, Zhang B, Ye J, Cao S, Shi J, Zhao Y, et al. Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression. Int J Biol Sci. 2019;15(11):2320–9.
Mochizuki S, Ao T, Sugiura T, Yonemura K, Shiraishi T, Kajiwara Y, et al. Expression and function of a disintegrin and Metalloproteinases in Cancer-Associated fibroblasts of Colorectal Cancer. Digestion. 2020;101(1):18–24.
Paauwe M, Schoonderwoerd MJA, Helderman R, Harryvan TJ, Groenewoud A, van Pelt GW, et al. Endoglin expression on Cancer-Associated fibroblasts regulates Invasion and stimulates colorectal Cancer Metastasis. Clin cancer Research: Official J Am Association Cancer Res. 2018;24(24):6331–44.
Ouahoud S, Voorneveld PW, van der Burg LRA, de Jonge-Muller ESM, Schoonderwoerd MJA, Paauwe M, et al. Bidirectional tumor/stroma crosstalk promotes metastasis in mesenchymal colorectal cancer. Oncogene. 2020;39(12):2453–66.
Hu JL, Wang W, Lan XL, Zeng ZC, Liang YS, Yan YR, et al. CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer. Mol Cancer. 2019;18(1):91.
Li R, Zhou J, Wu X, Li H, Pu Y, Liu N, et al. Jianpi Jiedu recipe inhibits colorectal cancer liver metastasis via regulating ITGBL1-rich extracellular vesicles mediated activation of cancer-associated fibroblasts. Phytomedicine: Int J Phytotherapy Phytopharmacology. 2022;100:154082.
Fang T, Lv H, Lv G, Li T, Wang C, Han Q, et al. Tumor-derived exosomal mir-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun. 2018;9(1):191.
Xu H, Zhao J, Li J, Zhu Z, Cui Z, Liu R, et al. Cancer associated fibroblast-derived CCL5 promotes hepatocellular carcinoma metastasis through activating HIF1α/ZEB1 axis. Cell Death Dis. 2022;13(5):478.
Kong J, Tian H, Zhang F, Zhang Z, Li J, Liu X, et al. Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts. Mol Cancer. 2019;18(1):175.
Ren Y, Jia HH, Xu YQ, Zhou X, Zhao XH, Wang YF, et al. Paracrine and epigenetic control of CAF-induced metastasis: the role of HOTAIR stimulated by TGF-ß1 secretion. Mol Cancer. 2018;17(1):5.
Chen L, Chen M, Han Z, Jiang F, Xu C, Qin Y, et al. Clinical significance of FAP-α on microvessel and lymphatic vessel density in lung squamous cell carcinoma. J Clin Pathol. 2018;71(8):721–8.
Ren Y, Cao L, Wang L, Zheng S, Zhang Q, Guo X, et al. Autophagic secretion of HMGB1 from cancer-associated fibroblasts promotes metastatic potential of non-small cell lung cancer cells via NFκB signaling. Cell Death Dis. 2021;12(10):858.
Richardson AM, Havel LS, Koyen AE, Konen JM, Shupe J, Wiles, WGt, et al. Vimentin is required for lung Adenocarcinoma Metastasis via Heterotypic Tumor Cell-Cancer-Associated Fibroblast Interactions during collective Invasion. Clin cancer Research: Official J Am Association Cancer Res. 2018;24(2):420–32.
Xue B, Chuang CH, Prosser HM, Fuziwara CS, Chan C, Sahasrabudhe N, et al. miR-200 deficiency promotes lung cancer metastasis by activating notch signaling in cancer-associated fibroblasts. Genes Dev. 2021;35(15–16):1109–22.
Ershaid N, Sharon Y, Doron H, Raz Y, Shani O, Cohen N, et al. NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis. Nat Commun. 2019;10(1):4375.
Bayer SV, Grither WR, Brenot A, Hwang PY, Barcus CE, Ernst M et al. DDR2 controls breast tumor stiffness and metastasis by regulating integrin mediated mechanotransduction in CAFs. eLife. 2019;8.
Chen B, Sang Y, Song X, Zhang D, Wang L, Zhao W, et al. Exosomal miR-500a-5p derived from cancer-associated fibroblasts promotes breast cancer cell proliferation and metastasis through targeting USP28. Theranostics. 2021;11(8):3932–47.
Yan Z, Sheng Z, Zheng Y, Feng R, Xiao Q, Shi L, et al. Cancer-associated fibroblast-derived exosomal miR-18b promotes breast cancer invasion and metastasis by regulating TCEAL7. Cell Death Dis. 2021;12(12):1120.
Chatterjee A, Jana S, Chatterjee S, Wastall LM, Mandal G, Nargis N, et al. MicroRNA-222 reprogrammed cancer-associated fibroblasts enhance growth and metastasis of breast cancer. Br J Cancer. 2019;121(8):679–89.
Wu HJ, Hao M, Yeo SK, Guan JL. FAK signaling in cancer-associated fibroblasts promotes breast cancer cell migration and metastasis by exosomal miRNAs-mediated intercellular communication. Oncogene. 2020;39(12):2539–49.
Wen S, Hou Y, Fu L, Xi L, Yang D, Zhao M, et al. Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell invasion and metastasis via integrin β3-p38 MAPK signalling. Cancer Lett. 2019;442:320–32.
Chen Y, Zeng C, Zhan Y, Wang H, Jiang X, Li W. Aberrant low expression of p85α in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b. Oncogene. 2017;36(33):4692–705.
Wang S, Englund E, Kjellman P, Li Z, Ahnlide JK, Rodriguez-Cupello C, et al. CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling. Nat Cell Biol. 2021;23(7):758–70.
Li X, Sun Z, Peng G, Xiao Y, Guo J, Wu B, et al. Single-cell RNA sequencing reveals a pro-invasive cancer-associated fibroblast subgroup associated with poor clinical outcomes in patients with gastric cancer. Theranostics. 2022;12(2):620–38.
Chen Y, Zhu S, Liu T, Zhang S, Lu J, Fan W, et al. Epithelial cells activate fibroblasts to promote esophageal cancer development. Cancer Cell. 2023;41(5):903–e188.
Li C, Guo H, Zhai P, Yan M, Liu C, Wang X, et al. Spatial and single-cell transcriptomics reveal a Cancer-Associated Fibroblast Subset in HNSCC that restricts infiltration and antitumor activity of CD8 + T cells. Cancer Res. 2024;84(2):258–75.
Honda CK, Kurozumi S, Fujii T, Pourquier D, Khellaf L, Boissiere F, et al. Cancer-associated fibroblast spatial heterogeneity and EMILIN1 expression in the tumor microenvironment modulate TGF-β activity and CD8(+) T-cell infiltration in breast cancer. Theranostics. 2024;14(5):1873–85.
Zhang H, Xie C, Yue J, Jiang Z, Zhou R, Xie R, et al. Cancer-associated fibroblasts mediated chemoresistance by a FOXO1/TGFβ1 signaling loop in esophageal squamous cell carcinoma. Mol Carcinog. 2017;56(3):1150–63.
Guillén Díaz-Maroto N, Sanz-Pamplona R, Berdiel-Acer M, Cimas FJ, García E, Gonçalves-Ribeiro S, et al. Noncanonical TGFβ pathway relieves the blockade of IL1β/TGFβ-Mediated crosstalk between Tumor and Stroma: TGFBR1 and TAK1 inhibition in Colorectal Cancer. Clin cancer Research: Official J Am Association Cancer Res. 2019;25(14):4466–79.
Ikemori R, Gabasa M, Duch P, Vizoso M, Bragado P, Arshakyan M, et al. Epigenetic SMAD3 repression in Tumor-Associated fibroblasts impairs fibrosis and response to the Antifibrotic Drug Nintedanib in Lung squamous cell carcinoma. Cancer Res. 2020;80(2):276–90.
Movia D, Bazou D, Prina-Mello A. ALI multilayered co-cultures mimic biochemical mechanisms of the cancer cell-fibroblast cross-talk involved in NSCLC MultiDrug Resistance. BMC Cancer. 2019;19(1):854.
Kodet O, Dvořánková B, Bendlová B, Sýkorová V, Krajsová I, Štork J, et al. Microenvironment–driven resistance to B–Raf inhibition in a melanoma patient is accompanied by broad changes of gene methylation and expression in distal fibroblasts. Int J Mol Med. 2018;41(5):2687–703.
Qiao Y, Zhang C, Li A, Wang D, Luo Z, Ping Y, et al. IL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophageal squamous cell carcinoma. Oncogene. 2018;37(7):873–83.
Ham IH, Oh HJ, Jin H, Bae CA, Jeon SM, Choi KS, et al. Targeting interleukin-6 as a strategy to overcome stroma-induced resistance to chemotherapy in gastric cancer. Mol Cancer. 2019;18(1):68.
Liu H, Shen J, Lu K. IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model. Biochem Biophys Res Commun. 2017;486(2):239–44.
Thongchot S, Ferraresi A, Vidoni C, Loilome W, Yongvanit P, Namwat N, et al. Resveratrol interrupts the pro-invasive communication between cancer associated fibroblasts and cholangiocarcinoma cells. Cancer Lett. 2018;430:160–71.
Li Z, Chan K, Qi Y, Lu L, Ning F, Wu M, et al. Participation of CCL1 in snail-positive fibroblasts in Colorectal Cancer contribute to 5-Fluorouracil/Paclitaxel Chemoresistance. Cancer Res Treat. 2018;50(3):894–907.
Che Y, Wang J, Li Y, Lu Z, Huang J, Sun S, et al. Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance. Cell Death Dis. 2018;9(7):759.
Masuda T, Nakashima T, Namba M, Yamaguchi K, Sakamoto S, Horimasu Y, et al. Inhibition of PAI-1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer-associated fibroblasts. J Cell Mol Med. 2019;23(4):2984–94.
Zhang Z, Karthaus WR, Lee YS, Gao VR, Wu C, Russo JW, et al. Tumor Microenvironment-Derived NRG1 promotes Antiandrogen Resistance in prostate Cancer. Cancer Cell. 2020;38(2):279–. – 96.e9.
Ogier C, Colombo PE, Bousquet C, Canterel-Thouennon L, Sicard P, Garambois V, et al. Targeting the NRG1/HER3 pathway in tumor cells and cancer-associated fibroblasts with an anti-neuregulin 1 antibody inhibits tumor growth in pre-clinical models of pancreatic cancer. Cancer Lett. 2018;432:227–36.
Wei L, Ye H, Li G, Lu Y, Zhou Q, Zheng S, et al. Cancer-associated fibroblasts promote progression and gemcitabine resistance via the SDF-1/SATB-1 pathway in pancreatic cancer. Cell Death Dis. 2018;9(11):1065.
You J, Li M, Cao LM, Gu QH, Deng PB, Tan Y, et al. Snail1-dependent cancer-associated fibroblasts induce epithelial-mesenchymal transition in lung cancer cells via exosomes. QJM: Monthly J Association Physicians. 2019;112(8):581–90.
Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 2017;36(13):1770–8.
Fang Y, Zhou W, Rong Y, Kuang T, Xu X, Wu W, et al. Exosomal miRNA-106b from cancer-associated fibroblast promotes gemcitabine resistance in pancreatic cancer. Exp Cell Res. 2019;383(1):111543.
Zhang T, Zhang P, Li HX. CAFs-Derived exosomal miRNA-130a confers Cisplatin Resistance of NSCLC cells through PUM2-Dependent packaging. Int J Nanomed. 2021;16:561–77.
Pan S, Deng Y, Fu J, Zhang Y, Zhang Z, Qin X. N6–methyladenosine upregulates miR–181d–5p in exosomes derived from cancer–associated fibroblasts to inhibit 5–FU sensitivity by targeting NCALD in colorectal cancer. Int J Oncol. 2022;60(2).
Zhou Z, Qu C, Zhou P, Zhou Q, Li D, Wu X, et al. Extracellular vesicles activated cancer-associated fibroblasts promote lung cancer metastasis through mitophagy and mtDNA transfer. J Exp Clin Cancer Res. 2024;43(1):158.
Zheng S, Wang J, Ding N, Chen W, Chen H, Xue M, et al. Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer. J Nanobiotechnol. 2021;19(1):381.
Guo J, Zeng H, Chen Y. Emerging Nano Drug Delivery systems Targeting Cancer-Associated fibroblasts for Improved Antitumor Effect and Tumor Drug Penetration. Mol Pharm. 2020;17(4):1028–48.
Chen B, Dai W, Mei D, Liu T, Li S, He B, et al. Comprehensively priming the tumor microenvironment by cancer-associated fibroblast-targeted liposomes for combined therapy with cancer cell-targeted chemotherapeutic drug delivery system. J Controlled Release: Official J Controlled Release Soc. 2016;241:68–80.
Zhou Q, Zhou Y, Liu X, Shen Y. GDC-0449 improves the antitumor activity of nano-doxorubicin in pancreatic cancer in a fibroblast-enriched microenvironment. Sci Rep. 2017;7(1):13379.
Peltanova B, Liskova M, Gumulec J, Raudenska M, Polanska HH, Vaculovic T et al. Sensitivity to Cisplatin in Head and Neck Cancer cells is significantly affected by patient-derived Cancer-Associated fibroblasts. Int J Mol Sci. 2021;22(4).
Benedicto A, Hernandez-Unzueta I, Sanz E, Márquez J. Ocoxin increases the Antitumor Effect of BRAF Inhibition and reduces Cancer Associated fibroblast-mediated Chemoresistance and Protumoral Activity in Metastatic Melanoma. Nutrients. 2021;13(2).
Zhou B, Sun C, Li N, Shan W, Lu H, Guo L, et al. Cisplatin-induced CCL5 secretion from CAFs promotes cisplatin-resistance in ovarian cancer via regulation of the STAT3 and PI3K/Akt signaling pathways. Int J Oncol. 2016;48(5):2087–97.
Zhang Y, Zhao J, Ding M, Su Y, Cui D, Jiang C, et al. Loss of exosomal miR-146a-5p from cancer-associated fibroblasts after androgen deprivation therapy contributes to prostate cancer metastasis. J Exp Clin Cancer Res. 2020;39(1):282.
Acknowledgements
not applicable.
Funding
This study was supported by grants from Henan Provincial Natural Science Foundation Youth Project (242300421487); Henan Provincial Medical Science and Technology Research Program Joint Construction Project (LHGJ20200276); Henan Medical Science and Technology Research Plan ( LHGJ20230294).
Author information
Authors and Affiliations
Contributions
Authors’ contribution: L.P., Y.S. and Y.W. drafted the work and wrote the main manuscript text; Y.W. and Y.S. made contributions to the conception or design of the work; L.P., G.X. and W.F. prepared Figs. 1, 2, 3, 4 and 5. and Table 1 in the work; W.F., Z.Q. and S.H. made contributions to the acquisition, analysis and interpretation of data; L.P., and Z.Q. made contributions to revise the manuscript text; All authors reviewed the manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
not applicable.
Consent for publication
not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Lyu, P., Gu, X., Wang, F. et al. Advances in targeting cancer-associated fibroblasts through single-cell spatial transcriptomic sequencing. Biomark Res 12, 73 (2024). https://doi.org/10.1186/s40364-024-00622-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s40364-024-00622-9