CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
Claire Vennin(Garvan Institute of Medical Research), Pauline Mélénec(Garvan Institute of Medical Research), Romain Rouet(Garvan Institute of Medical Research), Max Nobis(Garvan Institute of Medical Research), Aurélie Cazet(Garvan Institute of Medical Research), Kendelle J. Murphy(Garvan Institute of Medical Research), David Herrmann(Garvan Institute of Medical Research), Daniel A. Reed(Garvan Institute of Medical Research), Morghan C. Lucas(Garvan Institute of Medical Research), Sean Warren(Garvan Institute of Medical Research), Zehra Elgundi(UNSW Sydney), Mark Pinese(Garvan Institute of Medical Research), Gabriella Kalna(Cancer Research UK Scotland Institute), Daniel Roden(Garvan Institute of Medical Research), Monisha Samuel(La Trobe University), Anaiis Zaratzian(Garvan Institute of Medical Research), Shane T. Grey(Garvan Institute of Medical Research), Andrew Da Silva(Garvan Institute of Medical Research), Wilfred Leung(Garvan Institute of Medical Research), Australian Pancreatic Genome Initiative (APGI)(Garvan Institute of Medical Research), Amber L. Johns(Garvan Institute of Medical Research), Lorraine A. Chantrill(Garvan Institute of Medical Research), Angela Chou(Garvan Institute of Medical Research), Angela Steinmann(Garvan Institute of Medical Research), Mehreen Arshi(Garvan Institute of Medical Research), Tanya Dwarte(Garvan Institute of Medical Research), Danielle Froio(Garvan Institute of Medical Research), Brooke Pereira(Garvan Institute of Medical Research), Shona Ritchie(Garvan Institute of Medical Research), Cecilia R. Chambers(Garvan Institute of Medical Research), Xanthe L. Metcalf(Garvan Institute of Medical Research), Nicola Waddell(QIMR Berghofer Medical Research Institute), John V. Pearson(QIMR Berghofer Medical Research Institute), Ann-Marie Patch(QIMR Berghofer Medical Research Institute), Katia Nones(QIMR Berghofer Medical Research Institute), Felicity Newell(QIMR Berghofer Medical Research Institute), Pamela Mukhopadhyay(QIMR Berghofer Medical Research Institute), Venkateswar Addala(QIMR Berghofer Medical Research Institute), Stephen H. Kazakoff(QIMR Berghofer Medical Research Institute), Oliver Holmes(QIMR Berghofer Medical Research Institute), Conrad Leonard(QIMR Berghofer Medical Research Institute), Scott Wood(The University of Melbourne), Sean M. Grimmond(The University of Melbourne), Oliver Hofmann(The University of Queensland), Angelika N. Christ(The University of Queensland), Timothy J. C. Bruxner(The University of Queensland), Jaswinder S. Samra(Royal North Shore Hospital), Nick Pavlakis(Royal North Shore Hospital), Hilda A. High(Royal North Shore Hospital), Ray Asghari(Bankstown Lidcombe Hospital), Neil D. Merrett(Bankstown Lidcombe Hospital), Darren Pavey(Bankstown Lidcombe Hospital), Amitabha Das(Bankstown Lidcombe Hospital), Peter H. Cosman(Liverpool Hospital), Kasim Ismail(Liverpool Hospital), Chelsie O’Connnor(St Vincent's Hospital Sydney), Alina Stoita(St Vincent's Hospital Sydney), David Williams(St Vincent's Hospital Sydney), Allan Spigellman(Westmead Hospital), Vincent Lam(Westmead Hospital), Duncan McLeod(Westmead Hospital), Judy Kirk(Royal Prince Alfred Hospital), James G. Kench(Royal Prince Alfred Hospital), Peter Grimison(Royal Prince Alfred Hospital), Caroline Cooper(Royal Prince Alfred Hospital), Charbel Sandroussi(Royal Prince Alfred Hospital), Annabel Goodwin(Garvan Institute of Medical Research), R. Scott Mead(Garvan Institute of Medical Research), Katherine Tucker(Prince of Wales Hospital), Lesley Andrews(Fremantle Hospital), Michael Texler(Sir Charles Gairdner Hospital), Cindy Forest(Sir Charles Gairdner Hospital), Krishna Epari(Sir Charles Gairdner Hospital), Mo Ballal(Sir Charles Gairdner Hospital), David Fletcher(Sir Charles Gairdner Hospital), Sanjay Mukhedkar(St John of God Subiaco Hospital), Nikolajs Zeps(St John of God Subiaco Hospital), Maria Beilin(St John of God Subiaco Hospital), Kynan Feeney(St John of God Subiaco Hospital), Nan Q. Nguyen(Royal Adelaide Hospital), Andrew Ruszkiewicz(Royal Adelaide Hospital), Chris Worthley(Royal Adelaide Hospital), John Chen(Flinders Medical Centre), Mark E. Brooke‐Smith(Flinders Medical Centre), Virginia Papangelis(Flinders Medical Centre), Andrew D. Clouston(Princess Alexandra Hospital), Andrew P. Barbour(Princess Alexandra Hospital), Thomas J. O’Rourke(Princess Alexandra Hospital), Jonathan W. Fawcett(Princess Alexandra Hospital), Kellee Slater(Princess Alexandra Hospital), Michael Hatzifotis(Princess Alexandra Hospital), Peter Hodgkinson(Austin Hospital), Mehrdad Nikfarjam(Johns Hopkins University), James R. Eshleman(Johns Hopkins University), Ralph H. Hruban(Johns Hopkins University), Christopher L. Wolfgang(University of Verona), Rita T. Lawlor(University of Verona), Stefania Beghelli(University of Verona), Vincenzo Corbo(University of Verona), Maria Scardoni(University of Verona), Claudio Bassi(University of Verona), Andrew V. Biankin(Garvan Institute of Medical Research), Judith Dixon(Cancer Research UK Scotland Institute), Nigel B. Jamieson(Garvan Institute of Medical Research), David K. Chang(Garvan Institute of Medical Research), Suresh Mathivanan(La Trobe University), Yingxiao Wang(University of California San Diego), A. W. Braithwaite(Children's Medical Research Institute), Daniel Christ(Garvan Institute of Medical Research), Aleš Benda(UNSW Sydney), Ashleigh Parkin(Garvan Institute of Medical Research), Phoebe A. Phillips(UNSW Sydney), John M. Whitelock(UNSW Sydney), Anthony J. Gill(The University of Sydney), Owen J. Sansom(UNSW Sydney), David R. Croucher(The University of Sydney), Benjamin L. Parker(The University of Sydney), Marina Pajic(Garvan Institute of Medical Research), Jennifer P. Morton(UNSW Sydney), Thomas R. Cox(Garvan Institute of Medical Research), Paul Timpson(Garvan Institute of Medical Research)
Cited by 259Open Access
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.
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