Abstract
Cancer-associated fibroblasts (CAFs) found in primary and metastatic tumours are highly versatile, plastic and resilient cells that are actively involved in cancer progression through complex interactions with other cell types in the tumour microenvironment. As well as generating extracellular matrix components that contribute to the structure and function of the tumour stroma, CAFs undergo epigenetic changes to produce secreted factors, exosomes and metabolites that influence tumour angiogenesis, immunology and metabolism. Because of their putative pro-oncogenic functions, CAFs have long been considered an attractive therapeutic target; however, clinical trials of treatment strategies targeting CAFs have mostly ended in failure and, in some cases, accelerated cancer progression and resulted in inferior survival outcomes. Importantly, CAFs are heterogeneous cells and their characteristics and interactions with other cell types might change dynamically as cancers evolve. Studies involving single-cell RNA sequencing and novel mouse models have increased our understanding of CAF diversity, although the context-dependent roles of different CAF populations and their interchangeable plasticity remain largely unknown. Comprehensive characterization of the tumour-promoting and tumour-restraining activities of CAF subtypes, including how these complex bimodal functions evolve and are subjugated by neoplastic cells during cancer progression, might facilitate the development of novel diagnostic and therapeutic approaches. In this Review, the clinical relevance of CAFs is summarized with an emphasis on their value as prognosis factors and therapeutic targets.
Key points
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Cancer-associated fibroblasts (CAFs) are found in both primary and metastatic tumours; studies using modern cell sorting and sequencing technologies have provided exciting new insights into the potential therapeutic and prognostic value of CAFs.
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In particular, studies using single-cell RNA sequencing and genetically engineered mouse models have begun to reveal the heterogeneity and functional roles of CAFs, which are dynamic and context dependent.
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The precise functional roles of various CAF subtypes remain largely undefined, which requires future investigations integrating functional studies using multiple model systems with transcriptomic and/or proteomic data at single-cell resolution.
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The identification and precise characterization of the tumour-promoting and tumour-restraining functions of different CAF populations might provide opportunities to develop novel diagnostic and therapeutic approaches.
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References
Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat. Rev. Cancer 3, 422–433 (2003).
Madhavan, S. & Nagarajan, S. GRP78 and next generation cancer hallmarks: an underexplored molecular target in cancer chemoprevention research. Biochimie 175, 69–76 (2020).
Pietras, K. & Ostman, A. Hallmarks of cancer: interactions with the tumor stroma. Exp. Cell Res. 316, 1324–1331 (2010).
Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
Ronnov-Jessen, L., Petersen, O. W. & Bissell, M. J. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol. Rev. 76, 69–125 (1996).
Schulz, M., Salamero-Boix, A., Niesel, K., Alekseeva, T. & Sevenich, L. Microenvironmental regulation of tumor progression and therapeutic response in brain metastasis. Front. Immunol. 10, 1713 (2019).
Vong, S. & Kalluri, R. The role of stromal myofibroblast and extracellular matrix in tumor angiogenesis. Genes Cancer 2, 1139–1145 (2011).
Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002). A comprehensive review on the connection between inflammation and cancer.
Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).
Ohlund, D., Elyada, E. & Tuveson, D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211, 1503–1523 (2014). A comprehensive review on CAFs and their putative heterogeneity.
Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020). Article providing a consensus framework of CAF biology.
Bernard, V. et al. Single-cell transcriptomics of pancreatic cancer precursors demonstrates epithelial and microenvironmental heterogeneity as an early event in neoplastic progression. Clin. Cancer Res. 25, 2194–2205 (2019).
Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).
Hosein, A. N. et al. Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution. JCI Insight 5, e129212 (2019).
Peng, J. et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 29, 725–738 (2019).
Dominguez, C. X. et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov. 10, 232–253 (2020).
Li, H. et al. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat. Genet. 49, 708–718 (2017).
Zhang, L. et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell 181, 442–459.e29 (2020).
Puram, S. V. et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 171, 1611–1624.e24 (2017).
Bartoschek, M. et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat. Commun. 9, 5150 (2018).
Friedman, G. et al. Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4+ and PDPN+ CAFs to clinical outcome. Nat. Cancer 1, 692–708 (2020).
Kieffer, Y. et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 10, 1330–1351 (2020).
Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479.e10 (2018).
Lambrechts, D. et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24, 1277–1289 (2018).
Davidson, S. et al. Single-cell RNA sequencing reveals a dynamic stromal niche that supports tumor growth. Cell Rep. 31, 107628 (2020).
Chen, Z. et al. Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat. Commun. 11, 5077 (2020).
Virchow, R. Die cellularpathologie in ihrer begründung auf physiologische und pathologische gewebelehre. Zwanzig vorlesungen gehalten während der monate februar, märz und april 1858 im Pathologischen institute zu Berlin 440 (A. Hirschwald, 1858).
Tarin, D. & Croft, C. B. Ultrastructural features of wound healing in mouse skin. J. Anat. 105, 189–190 (1969).
Arina, A. et al. Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proc. Natl Acad. Sci. USA 113, 7551–7556 (2016).
Ronnov-Jessen, L. & Petersen, O. W. Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab. Invest. 68, 696–707 (1993).
Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).
Driskell, R. R. et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277–281 (2013).
Bachem, M. G. et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115, 421–432 (1998).
Apte, M. V. et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut 44, 534–541 (1999).
Yin, C., Evason, K. J., Asahina, K. & Stainier, D. Y. Hepatic stellate cells in liver development, regeneration, and cancer. J. Clin. Invest. 123, 1902–1910 (2013).
Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).
Mishra, P. J. et al. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res. 68, 4331–4339 (2008).
Quante, M. et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19, 257–272 (2011).
Raz, Y. et al. Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer. J. Exp. Med. 215, 3075–3093 (2018).
Zeisberg, E. M., Potenta, S., Xie, L., Zeisberg, M. & Kalluri, R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67, 10123–10128 (2007).
Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952–961 (2007).
Bochet, L. et al. Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res. 73, 5657–5668 (2013).
Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986). A comprehensive review on the connection between cancer and wound healing.
Ueba, T. et al. Transcriptional regulation of basic fibroblast growth factor gene by p53 in human glioblastoma and hepatocellular carcinoma cells. Proc. Natl Acad. Sci. USA 91, 9009–9013 (1994).
Mills, L. D. et al. Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J. Biol. Chem. 288, 11786–11794 (2013).
Cox, T. R. & Erler, J. T. Fibrosis and cancer: partners in crime or opposing forces? Trends Cancer 2, 279–282 (2016).
Schafer, M. & Werner, S. Cancer as an overhealing wound: an old hypothesis revisited. Nat. Rev. Mol. Cell Biol. 9, 628–638 (2008).
Sugimoto, H., Mundel, T. M., Kieran, M. W. & Kalluri, R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol. Ther. 5, 1640–1646 (2006). Early study revealing the putative heterogeneity of CAFs.
Kanzaki, R. & Pietras, K. Heterogeneity of cancer-associated fibroblasts: opportunities for precision medicine. Cancer Sci. 111, 2708–2717 (2020).
Biffi, G. & Tuveson, D. A. Diversity and biology of cancer-associated fibroblasts. Physiol. Rev. 101, 147–176 (2021).
Chen, S. et al. Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression. Nat. Cell Biol. 23, 87–98 (2021).
Affo, S. et al. Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 39, 866–882.e11 (2021).
Zhou, Y. et al. Single-cell multiomics sequencing reveals prevalent genomic alterations in tumor stromal cells of human colorectal cancer. Cancer Cell 38, 818–828.e5 (2020).
Chen, Y. et al. Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer Cell 39, 548–565.e6 (2021). Study showing that deletion of type I collagen in αSMA-expressing stromal cells exacerbates pancreatic cancer.
Wu, S. Z. et al. Stromal cell diversity associated with immune evasion in human triple-negative breast cancer. EMBO J. 39, e104063 (2020).
Ozdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).
Ohlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017). Study revealing that two distinct populations of CAFs exist in pancreatic cancer.
Monteran, L. & Erez, N. The dark side of fibroblasts: cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment. Front. Immunol. 10, 1835 (2019).
Umetsu, D. T., Katzen, D., Jabara, H. H. & Geha, R. S. Antigen presentation by human dermal fibroblasts: activation of resting T lymphocytes. J. Immunol. 136, 440–445 (1986).
Kundig, T. M. et al. Fibroblasts as efficient antigen-presenting cells in lymphoid organs. Science 268, 1343–1347 (1995).
Lakins, M. A., Ghorani, E., Munir, H., Martins, C. P. & Shields, J. D. Cancer-associated fibroblasts induce antigen-specific deletion of CD8+ T cells to protect tumour cells. Nat. Commun. 9, 948 (2018).
Nitta, T. et al. Fibroblasts as a source of self-antigens for central immune tolerance. Nat. Immunol. 21, 1172–1180 (2020).
Givel, A. M. et al. miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nat. Commun. 9, 1056 (2018).
Pelon, F. et al. Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms. Nat. Commun. 11, 404 (2020).
Su, S. et al. CD10+GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172, 841–856.e16 (2018).
Ligorio, M. et al. Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer. Cell 178, 160–175.e27 (2019).
Zhang, Z. et al. Tumor microenvironment-derived nrg1 promotes antiandrogen resistance in prostate cancer. Cancer Cell 38, 279–296.e9 (2020).
Francescone, R. et al. Netrin G1 promotes pancreatic tumorigenesis through cancer-associated fibroblast-driven nutritional support and immunosuppression. Cancer Discov. 11, 446–479 (2021).
Korc, M. Pancreatic cancer-associated stroma production. Am. J. Surg. 194, S84–S86 (2007).
Mahadevan, D. & Von Hoff, D. D. Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol. Cancer Ther. 6, 1186–1197 (2007).
Feig, C. et al. The pancreas cancer microenvironment. Clin. Cancer Res. 18, 4266–4276 (2012).
Whittle, M. C. & Hingorani, S. R. Fibroblasts in pancreatic ductal adenocarcinoma: biological mechanisms and therapeutic targets. Gastroenterology 156, 2085–2096 (2019).
Biffi, G. et al. IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 9, 282–301 (2019).
Shi, Y. et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 569, 131–135 (2019).
Cortot, A. B. et al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res. 73, 834–843 (2013).
Pein, M. et al. Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs. Nat. Commun. 11, 1494 (2020).
Ershaid, N. et al. NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis. Nat. Commun. 10, 4375 (2019).
Thomas, D. A. & Massague, J. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8, 369–380 (2005).
Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).
Mariathasan, S. et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).
O’Connell, J. T. et al. VEGF-A and Tenascin-C produced by S100A4+stromal cells are important for metastatic colonization. Proc. Natl Acad. Sci. USA 108, 16002–16007 (2011).
Tape, C. J. et al. Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell 165, 1818 (2016).
Bhowmick, N. A. et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848–851 (2004).
Boire, A. et al. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120, 303–313 (2005).
Sternlicht, M. D. et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98, 137–146 (1999).
Kumar, V. et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32, 654–668.e5 (2017).
Mhaidly, R. & Mechta-Grigoriou, F. Fibroblast heterogeneity in tumor micro-environment: role in immunosuppression and new therapies. Semin. Immunol. 48, 101417 (2020).
Fidler, I. J. et al. Modulation of tumor cell response to chemotherapy by the organ environment. Cancer Metastasis Rev. 13, 209–222 (1994).
Farmer, P. et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat. Med. 15, 68–74 (2009).
Meads, M. B., Gatenby, R. A. & Dalton, W. S. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat. Rev. Cancer 9, 665–674 (2009).
Vennin, C. et al. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. Nat. Commun. 10, 3637 (2019).
Heldin, C. H., Rubin, K., Pietras, K. & Ostman, A. High interstitial fluid pressure - an obstacle in cancer therapy. Nat. Rev. Cancer 4, 806–813 (2004).
Shimoda, M. et al. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat. Cell Biol. 16, 889–901 (2014).
Chauhan, V. P. et al. Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy. Proc. Natl Acad. Sci. USA 116, 10674–10680 (2019).
Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330, 827–830 (2010). Study showing that depletion of FAP-expressing stromal cells restores antitumour immunity.
Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013). Study reporting the immune-evasive functions of FAP-expressing CAFs mediated through CXCL12.
Yang, X. et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Cancer Res. 76, 4124–4135 (2016).
Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016).
Parker, S. J. et al. Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer. Cancer Discov. 10, 1018–1037 (2020).
Dalin, S. et al. Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance. Cancer Res. 79, 5723–5733 (2019).
Helms, E., Onate, M. K. & Sherman, M. H. Fibroblast heterogeneity in the pancreatic tumor microenvironment. Cancer Discov. 10, 648–656 (2020).
Bertero, T. et al. Tumor-stroma mechanics coordinate amino acid availability to sustain tumor growth and malignancy. Cell Metab. 29, 124–140.e10 (2019).
Auciello, F. R. et al. A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression. Cancer Discov. 9, 617–627 (2019).
Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).
Olivares, O. et al. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat. Commun. 8, 16031 (2017). References 101–108 report studies showing the regulatory functions of CAFs on cancer metabolism.
Kahlert, C. & Kalluri, R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J. Mol. Med. 91, 431–437 (2013).
Luga, V. & Wrana, J. L. Tumor-stroma interaction: revealing fibroblast-secreted exosomes as potent regulators of Wnt-planar cell polarity signaling in cancer metastasis. Cancer Res. 73, 6843–6847 (2013).
Hu, Y. et al. Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer. PLoS One 10, e0125625 (2015).
Richards, K. E. et al. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene 36, 1770–1778 (2017).
Zhao, H. et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife 5, e10250 (2016).
Mueller, M. M. & Fusenig, N. E. Friends or foes — bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).
Neesse, A., Algul, H., Tuveson, D. A. & Gress, T. M. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut 64, 1476–1484 (2015).
Laklai, H. et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 22, 497–505 (2016). Study demonstrating that pancreatic cancer genotypes can influence stromal extracellular matrix content, architecture and stiffness.
Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).
Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012). References 117 and 118 report that cancer cell-derived Hedgehog proteins act on stromal cells and αSMA-expressing stromal cells to restrain pancreatic cancer progression.
Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009). Study indicating that targeting of the tumour stroma through Hedgehog signalling in pancreatic cancer might improve the delivery of chemotherapeutics.
Lee, J. J. et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091–E3100 (2014).
Torphy, R. J. et al. Stromal content is correlated with tissue site, contrast retention, and survival in pancreatic adenocarcinoma. JCO Precis. Oncol. https://doi.org/10.1200/PO.17.00121 (2018).
Shin, K. et al. Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell 26, 521–533 (2014).
Bhattacharjee, S. et al. Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. J. Clin. Invest. 131, e146987 (2021).
Jiang, H. et al. Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix. J. Clin. Invest. 130, 4704–4709 (2020).
Armstrong, T. et al. Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin. Cancer Res. 10, 7427–7437 (2004).
Bachem, M. G. et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128, 907–921 (2005).
Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).
Egeblad, M., Rasch, M. G. & Weaver, V. M. Dynamic interplay between the collagen scaffold and tumor evolution. Curr. Opin. Cell Biol. 22, 697–706 (2010).
Catenacci, D. V. et al. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J. Clin. Oncol. 33, 4284–4292 (2015).
Ko, A. H. et al. A phase I study of FOLFIRINOX Plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma. Pancreas 45, 370–375 (2016).
Benson, A. B. III et al. A phase II randomized, double-blind, placebo-controlled study of simtuzumab or placebo in combination with gemcitabine for the first-line treatment of pancreatic adenocarcinoma. Oncologist 22, 241–e15 (2017).
Hecht, J. R. et al. A phase II, randomized, double-blind, placebo-controlled study of simtuzumab in combination with FOLFIRI for the second-line treatment of metastatic KRAS mutant colorectal adenocarcinoma. Oncologist 22, 243–e23 (2017).
Ramanathan, R. K. et al. Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J. Clin. Oncol. 37, 1062–1069 (2019).
Van Cutsem, E. et al. Randomized phase III trial of pegvorhyaluronidase Alfa with Nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma. J. Clin. Oncol. 38, 3185–3194 (2020).
Uhlen, M. et al. A pathology atlas of the human cancer transcriptome. Science 357, eaan2507 (2017).
Moinfar, F. et al. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res. 60, 2562–2566 (2000).
Kurose, K. et al. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat. Genet. 32, 355–357 (2002).
Patocs, A. et al. Breast-cancer stromal cells with TP53 mutations and nodal metastases. N. Engl. J. Med. 357, 2543–2551 (2007).
McAndrews, K. M., Chen, Y. & Kalluri, R. Stromal cells exhibit prevalent genetic aberrations in colorectal cancer. Cancer Cell 38, 774–775 (2020).
Bassez, A. et al. A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer. Nat. Med. 27, 820–832 (2021).
Zafar, H., Wang, Y., Nakhleh, L., Navin, N. & Chen, K. Monovar: single-nucleotide variant detection in single cells. Nat. Methods 13, 505–507 (2016).
Lodato, M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555–559 (2018).
Nam, A. S. et al. Somatic mutations and cell identity linked by Genotyping of Transcriptomes. Nature 571, 355–360 (2019).
Zhang, L. et al. Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. Proc. Natl Acad. Sci. USA 116, 9014–9019 (2019).
Froeling, F. E. et al. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression. Gastroenterology 141, 1486–1497 (2011).
Sherman, M. H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014). Study demonstrating that treatment with vitamin D can reprogramme CAFs to a quiescent state and enhance response to chemotherapy in models of pancreatic cancer.
Kiselev, V. Y., Andrews, T. S. & Hemberg, M. Challenges in unsupervised clustering of single-cell RNA-seq data. Nat. Rev. Genet. 20, 273–282 (2019). A comprehensive review on the challenges and caveats of single-cell RNA-sequencing data analysis.
Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–668 (2020).
Schonhuber, N. et al. A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat. Med. 20, 1340–1347 (2014).
Chen, Y. et al. Dual reporter genetic mouse models of pancreatic cancer identify an epithelial-to-mesenchymal transition-independent metastasis program. EMBO Mol. Med. 10, e9085 (2018).
Han, X. et al. A suite of new Dre recombinase drivers markedly expands the ability to perform intersectional genetic targeting. Cell Stem Cell 28, 1160–1176.e7 (2021).
Chen, Y. et al. Podoplanin+tumor lymphatics are rate limiting for breast cancer metastasis. PLoS Biol. 16, e2005907 (2018).
Hoshino, A. et al. Podoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progression. Cancer Res. 71, 4769–4779 (2011).
LeBleu, V. S. et al. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 19, 1047–1053 (2013).
Wendling, O., Bornert, J. M., Chambon, P. & Metzger, D. Efficient temporally-controlled targeted mutagenesis in smooth muscle cells of the adult mouse. Genesis 47, 14–18 (2009).
Garcia, P. E. et al. Differential contribution of pancreatic fibroblast subsets to the pancreatic cancer stroma. Cell Mol. Gastroenterol. Hepatol. 10, 581–599 (2020).
Kobayashi, H. et al. The balance of stromal BMP signaling mediated by GREM1 and ISLR drives colorectal carcinogenesis. Gastroenterology 160, 1224–1239.e30 (2021).
Mizutani, Y. et al. Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis. Cancer Res. 79, 5367–5381 (2019).
LeBleu, V. S. et al. Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis. Nat. Med. 19, 227–231 (2013).
Becker, L. M. et al. Epigenetic reprogramming of cancer-associated fibroblasts deregulates glucose metabolism and facilitates progression of breast cancer. Cell Rep. 31, 107701 (2020).
Mascharak, S. et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science 372, eaba2374 (2021).
Hirata, E. et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling. Cancer Cell 27, 574–588 (2015).
Lazard, D. et al. Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc. Natl Acad. Sci. USA 90, 999–1003 (1993).
Acknowledgements
The CAF-related work of the authors is supported by MD Anderson Cancer Center, and was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) award RP150231. The NIH National Cancer Institute grant P01CA117969 supports ECM-related research in the Kalluri laboratory.
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Chen, Y., McAndrews, K.M. & Kalluri, R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol 18, 792–804 (2021). https://doi.org/10.1038/s41571-021-00546-5
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DOI: https://doi.org/10.1038/s41571-021-00546-5
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