@article{109ecea3a52d45129a9be1da2293ca95,
title = "CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan",
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.",
keywords = "cancer, cancer microenvironment, cell biology",
author = "Claire Vennin and Pauline M{\'e}l{\'e}nec and Romain Rouet and Max Nobis and Cazet, {Aur{\'e}lie S.} and Murphy, {Kendelle J.} and David Herrmann and Reed, {Daniel A.} and Lucas, {Morghan C.} and Warren, {Sean C.} and Zehra Elgundi and Mark Pinese and Gabriella Kalna and Daniel Roden and Monisha Samuel and Anaiis Zaratzian and Grey, {Shane T.} and {Da Silva}, Andrew and Wilfred Leung and {Australian Pancreatic Genome Initiative (APGI)} and Johns, {Amber L.} and Chantrill, {Lorraine A.} and Angela Chou and Angela Steinmann and Mehreen Arshi and Tanya Dwarte and Danielle Froio and Brooke Pereira and Shona Ritchie and Chambers, {Cecilia R.} and Xanthe Metcalf and Nicola Waddell and Pearson, {John V.} and Patch, {Ann Marie} and Katia Nones and Felicity Newell and Pamela Mukhopadhyay and Venkateswar Addala and Stephen Kazakoff and Oliver Holmes and Conrad Leonard and Scott Wood and Grimmond, {Sean M.} and Oliver Hofmann and Angelika Christ and Tim Bruxner and Samra, {Jaswinder S.} and Nick Pavlakis and High, {Hilda A.} and Ray Asghari and Merrett, {Neil D.} and Darren Pavey and Amitabha Das and Cosman, {Peter H.} and Kasim Ismail and Chelsie O{\textquoteright}Connnor and Alina Stoita and David Williams and Allan Spigellman and Lam, {Vincent W.} and Duncan McLeod and Judy Kirk and Kench, {James G.} and Peter Grimison and Cooper, {Caroline L.} and Charbel Sandroussi and Annabel Goodwin and Mead, {R. Scott} and Katherine Tucker and Lesley Andrews and Michael Texler and Cindy Forest and Epari, {Krishna P.} and Mo Ballal and Fletcher, {David R.} and Sanjay Mukhedkar and Nikolajs Zeps and Maria Beilin and Kynan Feeney and Nguyen, {Nan Q.} and Ruszkiewicz, {Andrew R.} and Chris Worthley and John Chen and Brooke-Smith, {Mark E.} and Virginia Papangelis and Clouston, {Andrew D.} and Barbour, {Andrew P.} and O{\textquoteright}Rourke, {Thomas J.} and Fawcett, {Jonathan W.} and Kellee Slater and Michael Hatzifotis and Peter Hodgkinson and Mehrdad Nikfarjam and Eshleman, {James R.} and Hruban, {Ralph H.} and Wolfgang, {Christopher L.} and Lawlor, {Rita T.} and Stefania Beghelli and Vincenzo Corbo and Maria Scardoni and Claudio Bassi and Biankin, {Andrew V.} and Judith Dixon and Jamieson, {Nigel B.} and Chang, {David K.} and Suresh Mathivanan and Yingxiao Wang and Braithwaite, {Anthony W.} and Daniel Christ and Ales Benda and Ashleigh Parkin and Phillips, {Phoebe A.} and Whitelock, {John M.} and Gill, {Anthony J.} and Sansom, {Owen J.} and Croucher, {David R.} and Parker, {Benjamin L.} and Marina Pajic and Morton, {Jennifer P.} and Cox, {Thomas R.} and Paul Timpson",
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{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}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/. ",
year = "2019",
month = aug,
day = "12",
doi = "10.1038/s41467-019-10968-6",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature",
}