TGF-β- and IL-1-dependent fibroblast states differentially shape pancreatic cancer microenvironments and metastasis
- 1University of Cambridge
Abstract
Pancreatic ductal adenocarcinoma (PDAC) contains heterogeneous cancer-associated fibroblast (CAF) populations, including interleukin 1 (IL-1)-dependent inflammatory CAFs (iCAFs) and transforming growth factor beta (TGF-{beta})-dependent myofibroblastic CAFs (myCAFs), whose functions at primary and metastatic sites remain incompletely defined. Here, we genetically disrupted IL-1 or TGF-{beta} signalling in fibroblast activation protein (FAP)-expressing CAFs arising from a shared cellular origin to determine how myCAF and iCAF states shape PDAC progression and microenvironments. Depletion of TGF-{beta}-dependent myCAFs, but not IL-1-dependent iCAFs, did not alter primary tumour growth or local metastatic dissemination but significantly reduced liver and lung metastases. Matched primary tumours and liver metastasis analyses also revealed site-specific stromal responses to TGF-{beta} signalling disruption. Experimental models of liver metastasis colonisation and outgrowth indicated that the reduced metastatic phenotype was linked primarily to alterations within pancreatic tumours rather than to impaired malignant cell outgrowth at metastatic sites. Single-cell RNA-sequencing of myCAF-depleted primary tumours revealed extensive transcriptional reprogramming across fibroblast, immune and malignant compartments, highlighting the complexity of assigning myCAF-to-malignant cell signalling mechanisms in vivo. To resolve this crosstalk, we co-cultured PDAC organoids with pancreatic stellate cells engineered to remain in myCAF or iCAF states. Cross-model transcriptomic analyses, together with genetic and pharmacological perturbation studies, showed that myCAF-derived TGF-{beta} directly promotes epithelial-to-mesenchymal transition signalling in PDAC malignant cells, providing a candidate mechanism for the reduced metastasis observed upon myCAF depletion in vivo. These findings reveal distinct, context-dependent roles for TGF-{beta}- and IL-1-dependent CAF states and identify myCAF-derived TGF-{beta} signalling as a stromal mechanism promoting malignant cell plasticity.
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BibTeX
@misc{cheng2026tgfβ,
title = {{TGF-β- and IL-1-dependent fibroblast states differentially shape pancreatic cancer microenvironments and metastasis}},
author = {P. S. Cheng and E. G. Lloyd and M. Jihad and M. Zaccaria and K. Burgess and G. Mucciolo and S. Harish and W. Luo and J. S. Manansala and W. Li and J. Araos Henriquez and D. Mukherjee and S. Mills and P. M. Johnson and A. Alonso Montero and M. J. Duer and P. D. Kirk and M. Vallespinos and G. Biffi},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.750042},
url = {https://www.biorxiv.org/content/10.64898/2026.09.08.750042v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - TGF-β- and IL-1-dependent fibroblast states differentially shape pancreatic cancer microenvironments and metastasis
AU - P. S. Cheng
AU - E. G. Lloyd
AU - M. Jihad
AU - M. Zaccaria
AU - K. Burgess
AU - G. Mucciolo
AU - S. Harish
AU - W. Luo
AU - J. S. Manansala
AU - W. Li
AU - J. Araos Henriquez
AU - D. Mukherjee
AU - S. Mills
AU - P. M. Johnson
AU - A. Alonso Montero
AU - M. J. Duer
AU - P. D. Kirk
AU - M. Vallespinos
AU - G. Biffi
PY - 2026
DA - 2026/09/08
PB - bioRxiv
DO - 10.64898/2026.09.08.750042
UR - https://www.biorxiv.org/content/10.64898/2026.09.08.750042v1
AB - Pancreatic ductal adenocarcinoma (PDAC) contains heterogeneous cancer-associated fibroblast (CAF) populations, including interleukin 1 (IL-1)-dependent inflammatory CAFs (iCAFs) and transforming growth factor beta (TGF-{beta})-dependent myofibroblastic CAFs (myCAFs), whose functions at primary and metastatic sites remain incompletely defined. Here, we genetically disrupted IL-1 or TGF-{beta} signalling in fibroblast activation protein (FAP)-expressing CAFs arising from a shared cellular origin to determine how myCAF and iCAF states shape PDAC progression and microenvironments. Depletion of TGF-{beta}-dependent myCAFs, but not IL-1-dependent iCAFs, did not alter primary tumour growth or local metastatic dissemination but significantly reduced liver and lung metastases. Matched primary tumours and liver metastasis analyses also revealed site-specific stromal responses to TGF-{beta} signalling disruption. Experimental models of liver metastasis colonisation and outgrowth indicated that the reduced metastatic phenotype was linked primarily to alterations within pancreatic tumours rather than to impaired malignant cell outgrowth at metastatic sites. Single-cell RNA-sequencing of myCAF-depleted primary tumours revealed extensive transcriptional reprogramming across fibroblast, immune and malignant compartments, highlighting the complexity of assigning myCAF-to-malignant cell signalling mechanisms in vivo. To resolve this crosstalk, we co-cultured PDAC organoids with pancreatic stellate cells engineered to remain in myCAF or iCAF states. Cross-model transcriptomic analyses, together with genetic and pharmacological perturbation studies, showed that myCAF-derived TGF-{beta} directly promotes epithelial-to-mesenchymal transition signalling in PDAC malignant cells, providing a candidate mechanism for the reduced metastasis observed upon myCAF depletion in vivo. These findings reveal distinct, context-dependent roles for TGF-{beta}- and IL-1-dependent CAF states and identify myCAF-derived TGF-{beta} signalling as a stromal mechanism promoting malignant cell plasticity.
ER -