# Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival

Source: https://onco.cc/key-papers/paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014/  
OnCo record `paper-ozdemir-caf-depletion-accelerates-pancreatic-cancer-cancer-cell-2014` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: pancreatic-evidence
- Journal: Cancer Cell
- Year: 2014
- DOI: 10.1016/j.ccr.2014.04.005
- Authors: Özdemir BC, Pentcheva-Hoang T, Carstens JL, et al.
- 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.
- What it means: 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.

## Sources

- Cancer Cell 2014: https://doi.org/10.1016/j.ccr.2014.04.005
- PubMed: https://pubmed.ncbi.nlm.nih.gov/24856586/

## Connected records

- key papers: [Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma](https://onco.cc/key-papers/paper-halo-301-pegvorhyaluronidase-jco-2020/), [Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-moffitt-virtual-microdissection-subtypes-nat-genet-2015/)
- cancers: [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- targets: [FAP](https://onco.cc/targets/fap/)
- drugs: [Gemcitabine](https://onco.cc/drugs/gemcitabine/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/)
- institutions: [MD Anderson Cancer Center](https://onco.cc/institutions/md-anderson/)
- pathways: [Epithelial-mesenchymal transition & drug efflux](https://onco.cc/pathways/emt/), [Fibroblast activation, desmoplasia & matrix stiffness](https://onco.cc/pathways/caf-activation-desmoplasia/), [Tumour microenvironment (TME)](https://onco.cc/pathways/tumor-microenvironment/)
- terms: [Cancer-associated fibroblasts (CAFs)](https://onco.cc/terms/cancer-associated-fibroblasts/), [Desmoplasia (tumour stroma)](https://onco.cc/terms/desmoplasia/), [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Stroma-rich and desmoplastic tumours in molecular data](https://onco.cc/terms/desmoplastic-stroma-rich/)
- bottlenecks: [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/), [Failures are hidden](https://onco.cc/bottlenecks/b-negative-results/)
- journals: [Cancer Cell](https://onco.cc/journals/cancer-cell/)
- roadmaps: [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/)
- ideas: [Reprogramme the stroma rather than remove it: second-generation stromal trials with a stromal biomarker and a survival endpoint](https://onco.cc/ideas/idea-pdac-stromal-reprogramming-not-depletion/)

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