CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
Authors: 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. , Elgundi Zehra , Pinese Mark , Kalna Gabriella , Roden Daniel , Samuel Monisha , Zaratzian Anaiis , Grey Shane T. , Da Silva Andrew , Leung Wilfred ,   Australian Pancreatic Genome Initiative (APGI), Johns Amber L. , Chantrill Lorraine A. , Chou Angela , Steinmann Angela , Arshi Mehreen , Dwarte Tanya , Froio Danielle , Pereira Brooke , Ritchie Shona , Chambers Cecilia R , Metcalf Xanthe , Waddell Nicola , Pearson John V. , Patch Ann-Marie , Nones Katia , Newell Felicity , Mukhopadhyay Pamela , Addala Venkateswar , Kazakoff Stephen , Holmes Oliver , Leonard Conrad , Wood Scott , Grimmond Sean M. , Hofmann Oliver , Christ Angelika , Bruxner Tim , Samra Jaswinder S. , Pavlakis Nick , High Hilda A. , Asghari Ray , Merrett Neil D. , Pavey Darren , Das Amitabha , Cosman Peter H. , Ismail Kasim , O’Connnor Chelsie , Stoita Alina , Williams David , Spigellman Allan , Lam Vincent W. , McLeod Duncan , Kirk Judy , Kench James G. , Grimison Peter , Cooper Caroline L. , Sandroussi Charbel , Goodwin Annabel , Mead R. Scott , Tucker Katherine , Andrews Lesley , Texler Michael , Forest Cindy , Epari Krishna P. , Ballal Mo , Fletcher David R. , Mukhedkar Sanjay , Zeps Nikolajs , Beilin Maria , Feeney Kynan , Nguyen Nan Q. , Ruszkiewicz Andrew R. , Worthley Chris , Chen John , Brooke-Smith Mark E. , Papangelis Virginia , Clouston Andrew D. , Barbour Andrew P. , O’Rourke Thomas J. , Fawcett Jonathan W. , Slater Kellee , Hatzifotis Michael , Hodgkinson Peter , Nikfarjam Mehrdad , Eshleman James R. , Hruban Ralph H. , Wolfgang Christopher L. , Lawlor Rita T. , Beghelli Stefania , Corbo Vincenzo , Scardoni Maria , Bassi Claudio , Biankin Andrew V. , Dixon Judith , Jamieson Nigel B. , Chang David K. , Mathivanan Suresh , Wang Yingxiao , Braithwaite Anthony W. , Christ Daniel , Benda Ales , Parkin Ashleigh , 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 
Published: August 2019

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.