CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
Open accessAbstract
Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.
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Mutant p53 drives TNF production by cancer cells, leading to enhanced matrix remodelling and perlecan expression by CAFs.
“Mutant p53 drives TNF production by cancer cells, leading to enhanced matrix remodelling and perlecan expression by CAFs136.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [136]
In Results, “Paracrine signaling mediated by NFκB induces HSPG2 expression” (page unavailable), mutant-p53 cancer cells show increased TNFα secretion, and TNFα treatment increases HSPG2 (perlecan) expression in CAFs. The paper also reports enhanced matrix remodeling by CAFs educated by mutant-p53 cells, but does not establish that TNFα causes that remodeling; it describes the proposed paracrine mechanism as partly mediated by NFκB. (LLM, conf=0.83)
Experimental — accuracy not yet measuredKRAS mutation or different p53 mutational status can influence CAFs in PDAC.
“Work in PDAC has shown how KRAS mutation or different p53 mutational status can influence CAFs111,136.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [136]
Fibroblast status during tumorigenesis and progression can be influenced by genetic mutations present in PDAC cells.
“fibroblast status throughout tumorigenesis and progression can be influenced by genetic mutations present in the PDAC cells154,155”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [154]
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References 82 · Cited by 268
- Authors
- Vennin, C., Mélénec, P., Rouet, R., Nobis, M., Cazet, A. S., Murphy, K. J., Herrmann, D., Reed, D. A., Lucas, M. C., Warren, S. C., Elgundi, Z., Pinese, M., Kalna, G., Roden, D., Samuel, M., Zaratzian, A., Grey, S. T., Da Silva, A., Leung, W., (APGI), A. P. G. I., Johns, A. L., Chantrill, L. A., Chou, A., Steinmann, A., Arshi, M., Dwarte, T., Froio, D., Pereira, B., Ritchie, S., Chambers, C. R., Metcalf, X., Waddell, N., Pearson, J. V., Patch, A.-M., Nones, K., Newell, F., Mukhopadhyay, P., Addala, V., Kazakoff, S., Holmes, O., Leonard, C., Wood, S., Grimmond, S. M., Hofmann, O., Christ, A., Bruxner, T., Samra, J. S., Pavlakis, N., High, H. A., Asghari, R., Merrett, N. D., Pavey, D., Das, A., Cosman, P. H., Ismail, K., O’Connnor, C., Stoita, A., Williams, D., Spigellman, A., Lam, V. W., McLeod, D., Kirk, J., Kench, J. G., Grimison, P., Cooper, C. L., Sandroussi, C., Goodwin, A., Mead, R. S., Tucker, K., Andrews, L., Texler, M., Forest, C., Epari, K. P., Ballal, M., Fletcher, D. R., Mukhedkar, S., Zeps, N., Beilin, M., Feeney, K., Nguyen, N. Q., Ruszkiewicz, A. R., Worthley, C., Chen, J., Brooke-Smith, M. E., Papangelis, V., Clouston, A. D., Barbour, A. P., O’Rourke, T. J., Fawcett, J. W., Slater, K., Hatzifotis, M., Hodgkinson, P., Nikfarjam, M., Eshleman, J. R., Hruban, R. H., Wolfgang, C. L., Lawlor, R. T., Beghelli, S., Corbo, V., Scardoni, M., Bassi, C., Biankin, A. V., Dixon, J., Jamieson, N. B., Chang, D. K., Mathivanan, S., Wang, Y., Braithwaite, A. W., Christ, D., Benda, A., Parkin, A., Phillips, P. A., Whitelock, J. M., Gill, A. J., Sansom, O. J., Croucher, D. R., Parker, B. L., Pajic, M., Morton, J. P., Cox, T. R., & Timpson, P.
- Affiliations
- Garvan Institute of Medical Research (AU)
- UNSW Sydney (AU)
- Cancer Research UK Scotland Institute (GB)
- La Trobe University (AU)
- QIMR Berghofer Medical Research Institute (AU)
- The University of Melbourne (AU)
- The University of Queensland (AU)
- Royal North Shore Hospital (AU)
- Bankstown Lidcombe Hospital (AU)
- Liverpool Hospital (AU)
- St Vincent's Hospital Sydney (AU)
- Westmead Hospital (AU)
- Royal Prince Alfred Hospital (AU)
- Prince of Wales Hospital (AU)
- Fremantle Hospital (AU)
- Sir Charles Gairdner Hospital (AU)
- St John of God Subiaco Hospital (AU)
- Royal Adelaide Hospital (AU)
- Flinders Medical Centre (AU)
- Princess Alexandra Hospital (AU)
- Austin Hospital (AU)
- Johns Hopkins University (US)
- University of Verona (IT)
- University of Glasgow (GB)
- University of California San Diego (US)
- The University of Sydney (AU)
- Corresponding author
- Cox, Thomas R.
- Timpson, Paul
- ORCID
- Vennin, Claire
- Mélénec, Pauline
- Rouet, Romain
- Nobis, Max
- Cazet, Aurélie S.
- Murphy, Kendelle J.
- Herrmann, David
- Reed, Daniel A.
- Lucas, Morghan C.
- Warren, Sean C.
- Pinese, Mark
- Roden, Daniel
- Samuel, Monisha
- Grey, Shane T.
- Leung, Wilfred
- Johns, Amber L.
- Chantrill, Lorraine A.
- Chou, Angela
- Dwarte, Tanya
- Pereira, Brooke
- Chambers, Cecilia R
- Metcalf, Xanthe
- Waddell, Nicola
- Pearson, John V.
- Patch, Ann-Marie
- Newell, Felicity
- Mukhopadhyay, Pamela
- Addala, Venkateswar
- Kazakoff, Stephen
- Holmes, Oliver
- Leonard, Conrad
- Wood, Scott
- Grimmond, Sean M.
- Hofmann, Oliver
- Christ, Angelika
- Samra, Jaswinder S.
- Merrett, Neil D.
- Stoita, Alina
- Lam, Vincent W.
- McLeod, Duncan
- Kench, James G.
- Grimison, Peter
- Cooper, Caroline L.
- Sandroussi, Charbel
- Goodwin, Annabel
- Tucker, Katherine
- Andrews, Lesley
- Texler, Michael
- Fletcher, David R.
- Zeps, Nikolajs
- Ruszkiewicz, Andrew R.
- Chen, John
- Clouston, Andrew D.
- Barbour, Andrew P.
- Slater, Kellee
- Nikfarjam, Mehrdad
- Eshleman, James R.
- Hruban, Ralph H.
- Wolfgang, Christopher L.
- Lawlor, Rita T.
- Corbo, Vincenzo
- Biankin, Andrew V.
- Jamieson, Nigel B.
- Chang, David K.
- Mathivanan, Suresh
- Wang, Yingxiao
- Christ, Daniel
- Phillips, Phoebe A.
- Whitelock, John M.
- Gill, Anthony J.
- Sansom, Owen J.
- Croucher, David R.
- Parker, Benjamin L.
- Pajic, Marina
- Morton, Jennifer P.
- Cox, Thomas R.
- Timpson, Paul
- Venue
- Nature Communications
- Published
- 2019-08-12
- Volume
- 10
- Issue
- 1
- Pages
- 3637-3637
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6691013
- OpenAlex
- W2969111064
- Cited by
- 268
- References
- 82
- Citations by year
- 2026: 26 · 2025: 39 · 2024: 37 · 2023: 35 · 2022: 41 · 2021: 49 · 2020: 38 · 2019: 3
- FWCI
- 13.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Human Frontier Science Program
- Department of Health | National Health and Medical Research Council
- Cancer Council NSW
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- cancer-associated fibroblasts, pancreatic cancer, p53 status, CAF heterogeneity, perlecan, tumor microenvironment, metastasis, chemoresistance, intravital imaging
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Cell Movement, Mice, Inbred BALB C, Neoplasm Invasiveness, Pancreas, Pancreatic Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Drug Resistance, Neoplasm, Heparan Sulfate Proteoglycans, Cell Line, Tumor, Cell Proliferation, Mice
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