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

Claire Vennin, Pauline Melenec, Romain Rouet, Max Nobis, Aurelie 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) & 16 others 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

Research output: Contribution to journalArticle

9 Citations (Scopus)
13 Downloads (Pure)

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
Pages (from-to)1-22
Number of pages22
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 12 Aug 2019
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Cite this