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

C Vennin; P Mélénec; R Rouet; M Nobis; AS Cazet; KJ Murphy; D Herrmann; DA Reed; MC Lucas; SC Warren; Z Elgundi; M Pinese; G Kalna; D Roden; M Samuel; A Zaratzian; ST Grey; A Da Silva; W Leung; AL Johns; LA Chantrill; A Chou; A Steinmann; M Arshi; T Dwarte; D Froio; B Pereira; S Ritchie; CR Chambers; X Metcalf; N Waddell; JV Pearson; AM Patch; K Nones; F Newell; P Mukhopadhyay; V Addala; S Kazakoff; O Holmes; C Leonard; S Wood; SM Grimmond; O Hofmann; A Christ; T Bruxner; JS Samra; N Pavlakis; HA High; R Asghari; ND Merrett; D Pavey; A Das; PH Cosman; K Ismail; C O’Connnor; A Stoita; D Williams; A Spigellman; VW Lam; D McLeod; J Kirk; JG Kench; P Grimison; CL Cooper; C Sandroussi; A Goodwin; RS Mead; K Tucker; L Andrews; M Texler; C Forest; KP Epari; M Ballal; DR Fletcher; S Mukhedkar; N Zeps; M Beilin; K Feeney; NQ Nguyen; AR Ruszkiewicz; C Worthley; J Chen; ME Brooke-Smith; V Papangelis; AD Clouston; AP Barbour; TJ O’Rourke; JW Fawcett; K Slater; M Hatzifotis; P Hodgkinson; M Nikfarjam; JR Eshleman; RH Hruban; CL Wolfgang; RT Lawlor; S Beghelli; V Corbo; M Scardoni; C Bassi

Journal article

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

C Vennin, P Mélénec, R Rouet, M Nobis, AS Cazet, KJ Murphy, D Herrmann, DA Reed, MC Lucas, SC Warren, Z Elgundi, M Pinese, G Kalna, D Roden, M Samuel, A Zaratzian, ST Grey, A Da Silva, W Leung, AL Johns Show all

Nature Communications | NATURE PORTFOLIO | Published : 2019

DOI: 10.1038/s41467-019-10968-6

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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 in..

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University of Melbourne Researchers

Sean Grimmond Author

Oliver Hofmann Author

Mehrdad Nikfarjam Author

Grants

Awarded by National Institutes of Health

Funding Acknowledgements

The authors wish to thank Brooke Pereira, Shona Ritchie and Cecilia Chambers for critical reading of the manuscript. This work was supported by NHMRC, Cancer Council NSW, Cancer Institute NSW (M.N., D.H., and T.R.C), Len Ainsworth Pancreatic Cancer Fellowship (P.T.) and Philip Hemstritch Pancreatic Cancer Fellowship (M.P.), Royal Australasian College of Physicians Research Foundation scholarships, a CRUK core grant, an NBCF fellowship (D.R.). This project was made possible by an Avner Pancreatic Cancer Foundation Grant. P.T. is a recipient of an NHMRC Senior Research Fellowship, C.V. is a recipient of a post-doctoral HFSP fellowship, T.R.C. is a recipient of an NHMRC RD Wright Biomedical Career Development Fellowship, A.W.B. was supported by the Royal Society of NZ James Cook Fellowship and Health Research Council of NZ research grants. Y.W. was supported by a United States NIH CA204704 and CA209629. B.L.P. is a recipient of an NHMRC Early Career Fellowship.