{"entity":{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","aka":[],"tldr":"Tumours recruit the body's repair cells, fibroblasts, and keep them in wound-healing mode forever. The scar tissue they lay down (desmoplasia) squeezes blood vessels shut, walls out immune cells, stiffens the tissue in a way that itself tells cancer cells to grow, and is why pancreatic cancer is so hard to treat.","summary":"Resident fibroblasts, pancreatic and hepatic stellate cells, and mesenchymal stromal cells are activated by TGF-β, PDGF, IL-1, Hedgehog ligand from tumour cells and by stiffness itself (YAP/TAZ feed-forward) into myofibroblastic CAFs (myCAF: αSMA, collagen I/III, FAP, LRRC15), inflammatory CAFs (iCAF: IL-6, LIF, CXCL12, driven by IL-1/JAK-STAT) and antigen-presenting CAFs. They deposit and crosslink collagen (LOX/LOXL2), hyaluronan and fibronectin, raising interstitial pressure (collapsing vessels, blocking drug delivery) and stiffness, which signals through integrins → FAK → RHO → YAP/TAZ to drive proliferation, EMT and chemoresistance in tumour cells; aligned fibres guide invasion; TGF-β-CAFs exclude T cells. CAFs also feed tumours (alanine, lipids, exosomes) and shield them. Depleting all fibroblasts (Shh-deleted or αSMA-ablated mice) made tumours more aggressive, and the SMO inhibitor vismodegib and hyaluronidase PEGPH20 failed in PDAC: hence a shift to reprogramming (vitamin D receptor agonists, losartan/angiotensin blockade in trials, IL-1/JAK for iCAF, LRRC15 or FAP targeting with radioligands and CAR-T) and to exploiting FAP for imaging (FAPI PET) and therapy.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Cancer-associated_fibroblast","links":[{"label":"Sahai et al., A framework for advancing our understanding of cancer-associated fibroblasts (Nat Rev Cancer 2020)","url":"https://doi.org/10.1038/s41568-019-0238-1"},{"label":"Kalluri, The biology and function of fibroblasts in cancer (Nat Rev Cancer 2016)","url":"https://doi.org/10.1038/nrc.2016.73"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["pancreatic","cholangiocarcinoma","breast-hr-positive"],"sections":[],"technologies":["fapi-pet","stroma-directed-car","mechanobiology-therapy","radioligand-therapy","single-cell-spatial"],"targets":["fap","smoothened","jak2","pd1"],"drugs":["fap-2286","vismodegib","sonidegib","ruxolitinib","avutometinib-defactinib"],"companies":[],"institutions":[],"pathways":["tumor-microenvironment","tgf-beta","hippo-yap","hedgehog","jak-stat","immune-desert-exclusion","invasion-ecm-degradation"],"terms":["desmoplasia","cancer-associated-fibroblasts","immune-exclusion","cold-vs-hot"],"trials":[],"people":[],"bottlenecks":["b-tme-immunosuppression"],"keyPapers":["paper-kalluri-nat-rev-cancer","paper-sahai-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"analogy":"Builders hired to repair a wall who never stop: they pour concrete around the tumour until the roads are blocked (vessels), the police cannot get in (T cells), and the very hardness of the concrete tells the tenants to multiply. Demolishing the builders' work made things worse; the newer plan is to retrain them.","nodes":[{"id":"tum","label":"Tumour: TGF-β, PDGF, Hh, IL-1","x":12,"y":15},{"id":"fib","label":"Fibroblast / stellate cell","x":45,"y":15},{"id":"my","label":"myCAF (FAP, αSMA, collagen)","x":78,"y":15,"targetId":"fap"},{"id":"icaf","label":"iCAF (IL-6, CXCL12, LIF)","x":78,"y":48,"targetId":"jak2"},{"id":"ecm","label":"Collagen, HA, LOX crosslinks","x":45,"y":48},{"id":"stiff","label":"Stiffness → FAK → YAP/TAZ","x":12,"y":48},{"id":"press","label":"Pressure: vessels collapse","x":45,"y":82},{"id":"excl","label":"T-cell exclusion","x":78,"y":82,"targetId":"pd1"},{"id":"grow","label":"Growth, EMT, chemoresistance","x":12,"y":82},{"id":"smo","label":"Hedgehog (SMO) paradox","x":12,"y":96,"targetId":"smoothened"}],"edges":[{"from":"tum","to":"fib","type":"activates"},{"from":"fib","to":"my","type":"activates"},{"from":"fib","to":"icaf","type":"activates"},{"from":"my","to":"ecm","type":"activates"},{"from":"ecm","to":"stiff","type":"activates"},{"from":"stiff","to":"grow","type":"activates"},{"from":"stiff","to":"fib","type":"activates"},{"from":"ecm","to":"press","type":"activates"},{"from":"my","to":"excl","type":"activates"},{"from":"icaf","to":"excl","type":"activates"},{"from":"smo","to":"fib","type":"activates"}],"interventions":["FAP-targeted imaging (FAPI PET) and radioligands (FAP-2286) and FAP/LRRC15 CAR-T","Reprogramming: vitamin D analogues, losartan with chemoradiation (PDAC trials), IL-1/JAK inhibition for iCAFs","FAK inhibitors soften stroma and improve immunotherapy entry (trials); mechanobiology approaches","Vismodegib and PEGPH20 failed in PDAC: stromal depletion can accelerate disease"]},"route":"/pathways/caf-activation-desmoplasia/","neighbours":{"cancer":[{"id":"cholangiocarcinoma","kind":"cancer","name":"Biliary tract cancer (cholangiocarcinoma)","route":"/cancers/cholangiocarcinoma/"},{"id":"borderline-resectable-pdac","kind":"cancer","name":"Borderline resectable pancreatic ductal adenocarcinoma","route":"/cancers/borderline-resectable-pdac/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"locally-advanced-pdac","kind":"cancer","name":"Locally advanced unresectable pancreatic ductal adenocarcinoma","route":"/cancers/locally-advanced-pdac/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"technology":[{"id":"stroma-directed-car","kind":"technology","name":"CAR-T against stroma: fibroblasts and myeloid cells","route":"/technologies/stroma-directed-car/"},{"id":"fapi-pet","kind":"technology","name":"FAPI PET","route":"/technologies/fapi-pet/"},{"id":"radioligand-therapy","kind":"technology","name":"Radioligand therapy (beta emitters)","route":"/technologies/radioligand-therapy/"},{"id":"single-cell-spatial","kind":"technology","name":"Single-cell & spatial profiling","route":"/technologies/single-cell-spatial/"},{"id":"mechanobiology-therapy","kind":"technology","name":"Targeting tumour mechanics and pressure","route":"/technologies/mechanobiology-therapy/"}],"target":[{"id":"fap","kind":"target","name":"FAP","route":"/targets/fap/"},{"id":"jak2","kind":"target","name":"JAK2","route":"/targets/jak2/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"smoothened","kind":"target","name":"Smoothened (hedgehog pathway)","route":"/targets/smoothened/"}],"drug":[{"id":"avutometinib-defactinib","kind":"drug","name":"Avutometinib + defactinib","route":"/drugs/avutometinib-defactinib/"},{"id":"fap-2286","kind":"drug","name":"FAP-2286 (177Lu / 68Ga)","route":"/drugs/fap-2286/"},{"id":"ruxolitinib","kind":"drug","name":"Ruxolitinib","route":"/drugs/ruxolitinib/"},{"id":"sonidegib","kind":"drug","name":"Sonidegib","route":"/drugs/sonidegib/"},{"id":"vismodegib","kind":"drug","name":"Vismodegib","route":"/drugs/vismodegib/"}],"pathway":[{"id":"immune-desert-exclusion","kind":"pathway","name":"Cold tumours: immune deserts and exclusion","route":"/pathways/immune-desert-exclusion/"},{"id":"hedgehog","kind":"pathway","name":"Hedgehog signalling","route":"/pathways/hedgehog/"},{"id":"hippo-yap","kind":"pathway","name":"Hippo-YAP/TAZ","route":"/pathways/hippo-yap/"},{"id":"invasion-ecm-degradation","kind":"pathway","name":"Invasion: proteases, adhesion & the invasive front","route":"/pathways/invasion-ecm-degradation/"},{"id":"jak-stat","kind":"pathway","name":"JAK-STAT signalling","route":"/pathways/jak-stat/"},{"id":"tgf-beta","kind":"pathway","name":"TGF-β signalling","route":"/pathways/tgf-beta/"},{"id":"theories-of-cancer","kind":"pathway","name":"Theories of cancer: how the ideas connect","route":"/pathways/theories-of-cancer/"},{"id":"tumor-microenvironment","kind":"pathway","name":"Tumour microenvironment (TME)","route":"/pathways/tumor-microenvironment/"}],"term":[{"id":"cancer-associated-fibroblasts","kind":"term","name":"Cancer-associated fibroblasts (CAFs)","route":"/terms/cancer-associated-fibroblasts/"},{"id":"desmoplasia","kind":"term","name":"Desmoplasia (tumour stroma)","route":"/terms/desmoplasia/"},{"id":"caf-subtypes-pancreatic","kind":"term","name":"Fibroblast subtypes in the pancreatic cancer stroma (myCAF, iCAF and apCAF)","route":"/terms/caf-subtypes-pancreatic/"},{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"immune-exclusion","kind":"term","name":"Immune exclusion","route":"/terms/immune-exclusion/"},{"id":"mechanical-theory-of-cancer","kind":"term","name":"Mechanical theory: stiffness, pressure and force as causes","route":"/terms/mechanical-theory-of-cancer/"},{"id":"microenvironment-inflammation-theory","kind":"term","name":"Microenvironment and inflammation: tumours as wounds that do not heal","route":"/terms/microenvironment-inflammation-theory/"},{"id":"desmoplastic-stroma-rich","kind":"term","name":"Stroma-rich and desmoplastic tumours in molecular data","route":"/terms/desmoplastic-stroma-rich/"},{"id":"tissue-organisation-field-theory","kind":"term","name":"Tissue organisation field theory (Sonnenschein and Soto)","route":"/terms/tissue-organisation-field-theory/"}],"bottleneck":[{"id":"b-tme-immunosuppression","kind":"bottleneck","name":"Cold tumours and the immunosuppressive microenvironment","route":"/bottlenecks/b-tme-immunosuppression/"}],"paper":[{"id":"paper-sahai-nat-rev-cancer","kind":"paper","name":"A framework for 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cancer","route":"/key-papers/paper-ohlund-caf-subtypes-mycaf-icaf-jem-2017/"},{"id":"paper-olive-hedgehog-stroma-gemcitabine-delivery-science-2009","kind":"paper","name":"Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer","route":"/key-papers/paper-olive-hedgehog-stroma-gemcitabine-delivery-science-2009/"},{"id":"paper-halo-301-pegvorhyaluronidase-jco-2020","kind":"paper","name":"Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma","route":"/key-papers/paper-halo-301-pegvorhyaluronidase-jco-2020/"},{"id":"paper-grunwald-subtme-pancreatic-cell-2021","kind":"paper","name":"Spatially confined sub-tumor microenvironments in pancreatic 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cancer","route":"/key-papers/paper-cms-guinney-nat-med-2015/"},{"id":"paper-ho-pancreatic-tumour-microenvironment-review-nrco-2020","kind":"paper","name":"The tumour microenvironment in pancreatic cancer: clinical challenges and opportunities","route":"/key-papers/paper-ho-pancreatic-tumour-microenvironment-review-nrco-2020/"},{"id":"paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015","kind":"paper","name":"Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma","route":"/key-papers/paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015/"}]}}