{"entity":{"id":"paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014","kind":"paper","name":"Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival","aka":[],"tldr":"The 2014 mouse study showing that removing the scar-forming cells around pancreatic tumours made the cancers more aggressive and the mice die sooner, the warning that the stroma is not simply an obstacle to be cleared.","summary":"Özdemir and colleagues in Raghu Kalluri's laboratory generated transgenic mice able to delete alpha-SMA-positive myofibroblasts in pancreatic cancer. Depletion starting at either the precursor (pancreatic intraepithelial neoplasia) or the invasive stage led to invasive, undifferentiated tumours with enhanced hypoxia, epithelial-to-mesenchymal transition and cancer stem cells, and shortened survival. In patients, fewer myofibroblasts in the tumour also correlated with reduced survival. Depleted tumours had suppressed immune surveillance with more CD4-positive Foxp3-positive regulatory T cells; they did not respond to gemcitabine, but anti-CTLA4 immunotherapy reversed the acceleration and prolonged survival. The authors underscore the need for caution in targeting carcinoma-associated fibroblasts.","asOf":"2026-09-24","links":[{"label":"Cancer Cell 2014","url":"https://doi.org/10.1016/j.ccr.2014.04.005"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/24856586/"}],"tags":["pancreatic-evidence"],"related":["paper-halo-301-pegvorhyaluronidase-jco-2020","paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015"],"cancers":["pancreatic"],"sections":[],"technologies":[],"targets":["fap"],"drugs":["gemcitabine","ipilimumab"],"companies":[],"institutions":["md-anderson"],"pathways":["emt","caf-activation-desmoplasia","tumor-microenvironment"],"terms":["desmoplasia","desmoplastic-stroma-rich","cancer-associated-fibroblasts","cold-vs-hot"],"trials":[],"people":[],"bottlenecks":["b-tme-immunosuppression","b-negative-results"],"keyPapers":[],"journals":["cancer-cell"],"dependsOn":[],"notes":[],"journal":"Cancer Cell","year":2014,"doi":"10.1016/j.ccr.2014.04.005","pmid":"24856586","authors":"Özdemir BC, Pentcheva-Hoang T, Carstens JL, et al.","paperType":"basic","findings":["Myofibroblast depletion in mice produced undifferentiated, hypoxic tumours and shorter survival.","Fewer myofibroblasts in human tumours also correlated with worse survival.","Depleted tumours were gemcitabine-resistant but responded to anti-CTLA4."],"whatItMeans":"Together with the negative HALO-301 trial of hyaluronidase this ended the first, blunt version of stromal targeting; second-generation ideas aim to reprogramme rather than remove the stroma.","caveats":["Mouse genetics; the human correlation is observational.","Stroma is heterogeneous (Moffitt's normal and activated subtypes); depleting one cell type says little about targeting a matrix component."],"changedPractice":true},"route":"/key-papers/paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014/","neighbours":{"paper":[{"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-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/"}],"cancer":[{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"target":[{"id":"fap","kind":"target","name":"FAP","route":"/targets/fap/"}],"drug":[{"id":"gemcitabine","kind":"drug","name":"Gemcitabine","route":"/drugs/gemcitabine/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"}],"institution":[{"id":"md-anderson","kind":"institution","name":"MD Anderson Cancer Center","route":"/institutions/md-anderson/"}],"pathway":[{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","route":"/pathways/caf-activation-desmoplasia/"},{"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":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"desmoplastic-stroma-rich","kind":"term","name":"Stroma-rich and desmoplastic tumours in molecular data","route":"/terms/desmoplastic-stroma-rich/"}],"bottleneck":[{"id":"b-tme-immunosuppression","kind":"bottleneck","name":"Cold tumours and the immunosuppressive microenvironment","route":"/bottlenecks/b-tme-immunosuppression/"},{"id":"b-negative-results","kind":"bottleneck","name":"Failures are hidden","route":"/bottlenecks/b-negative-results/"}],"journal":[{"id":"cancer-cell","kind":"journal","name":"Cancer Cell","route":"/journals/cancer-cell/"}],"roadmap":[{"id":"pancreatic-roadmap","kind":"roadmap","name":"Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question","route":"/roadmaps/pancreatic-roadmap/"}],"idea":[{"id":"idea-pdac-stromal-reprogramming-not-depletion","kind":"idea","name":"Reprogramme the stroma rather than remove it: second-generation stromal trials with a stromal biomarker and a survival endpoint","route":"/ideas/idea-pdac-stromal-reprogramming-not-depletion/"}]}}