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

Claire Vennin, Pauline Mélénec, Romain Rouet, Max Nobis, Aurélie 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 Silva, Wilfred Leung, 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 () and Paul Timpson ()
Additional contact information
Claire Vennin: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Pauline Mélénec: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Romain Rouet: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Max Nobis: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Aurélie S. Cazet: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Kendelle J. Murphy: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
David Herrmann: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Daniel A. Reed: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Morghan C. Lucas: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Sean C. Warren: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Zehra Elgundi: University of New South Wales Sydney
Mark Pinese: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Gabriella Kalna: Cancer Research UK Beatson Institute
Daniel Roden: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Monisha Samuel: La Trobe University
Anaiis Zaratzian: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Shane T. Grey: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Andrew Silva: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Wilfred Leung: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Suresh Mathivanan: La Trobe University
Yingxiao Wang: University of California
Anthony W. Braithwaite: University of Sydney
Daniel Christ: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Ales Benda: University of New South Wales
Ashleigh Parkin: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Phoebe A. Phillips: University of New South Wales
John M. Whitelock: University of New South Wales Sydney
Anthony J. Gill: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Owen J. Sansom: Cancer Research UK Beatson Institute
David R. Croucher: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Benjamin L. Parker: the University of Sydney
Marina Pajic: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Jennifer P. Morton: Cancer Research UK Beatson Institute
Thomas R. Cox: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre
Paul Timpson: The Garvan Institute of Medical Research & The Kinghorn Cancer Centre

Nature Communications, 2019, vol. 10, issue 1, 1-22

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10968-6

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