| Literature DB >> 31406163 |
Claire Vennin1,2,3, Pauline Mélénec1,2, Romain Rouet1,2, Max Nobis1,2, Aurélie S Cazet1,2, Kendelle J Murphy1,2, David Herrmann1,2, Daniel A Reed1,2, Morghan C Lucas1,2, Sean C Warren1,2, Zehra Elgundi4, Mark Pinese1,2, Gabriella Kalna5, Daniel Roden1,2, Monisha Samuel6, Anaiis Zaratzian1, Shane T Grey1,2, Andrew Da Silva1, Wilfred Leung1,2,7, Suresh Mathivanan6, Yingxiao Wang8, Anthony W Braithwaite9,10,11, Daniel Christ1,2, Ales Benda12, Ashleigh Parkin1,2, Phoebe A Phillips13,14, John M Whitelock4, Anthony J Gill1,15,16,17, Owen J Sansom5, David R Croucher1,2, Benjamin L Parker18, Marina Pajic1,2, Jennifer P Morton5, Thomas R Cox19,20, Paul Timpson21,22.
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.Entities:
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Year: 2019 PMID： 31406163 PMCID： PMC6691013 DOI： 10.1038/s41467-019-10968-6
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919