CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan

Claire Vennin, Pauline Mélénec, Romain Rouet, Max Nobis, Aurélie S. Cazet, Kendelle J. Murphy, David Herrmann, Daniel A. Reed, Morghan C. Lucas, Sean C. Warren, Zehra Elgundi, Mark Pinese, Gabriella Kalna, Daniel Roden, Monisha Samuel, Anaiis Zaratzian, Shane T. Grey, Andrew Da Silva, Wilfred Leung, Australian Pancreatic Genome Initiative (APGI)John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Suresh Mathivanan, Yingxiao Wang, Anthony W. Braithwaite, Daniel Christ, Ales Benda, Ashleigh Parkin, Phoebe A. Phillips, John M. Whitelock, Anthony J. Gill, Owen J. Sansom, David R. Croucher, Benjamin L. Parker, Marina Pajic, Jennifer P. Morton, Thomas R. Cox, Paul Timpson

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Abstract

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.

Original languageEnglish
Article number3637
Number of pages22
JournalNature Communications
Volume10
DOIs
Publication statusPublished - 12 Aug 2019
Externally publishedYes

Bibliographical note

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Keywords

  • cancer
  • cancer microenvironment
  • cell biology

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    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., ... Timpson, P. (2019). CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. Nature Communications, 10, [3637]. https://doi.org/10.1038/s41467-019-10968-6