1. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
- Author
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Vennin, C, Melenec, P, Rouet, R, Nobis, M, Cazet, As, Murphy, Kj, Herrmann, D, Reed, Da, Lucas, Mc, Warren, Sc, Elgundi, Z, Pinese, M, Kalna, G, Roden, D, Samuel, M, Zaratzian, A, Grey, St, Da Silva, A, Leung, W, Mathivanan, S, Wang, Yx, Braithwaite, Aw, Christ, D, Benda, A, Parkin, A, Phillips, Pa, Whitelock, Jm, Gill, Aj, Sansom, Oj, Croucher, Dr, Parker, Bl, Pajic, M, Morton, Jp, Cox, Tr, Timpson, P, Johns, Al, Chantrill, La, Chou, A, Steinmann, A, Arshi, M, Dwarte, T, Froio, D, Pereira, B, Ritchie, S, Chambers, Cr, Metcalf, X, Waddell, N, Pearson, Jv, Patch, Am, Nones, K, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Leonard, C, Wood, S, Grimmond, Sm, Hofmann, O, Christ, A, Bruxner, T, Samra, Js, Pavlakis, N, High, Ha, Asghari, R, Merrett, Nd, Pavey, D, Das, A, Cosman, Ph, Ismail, K, O'Connnor, C, Stoita, A, Williams, D, Spigellman, A, Lam, Vw, Mcleod, D, Kirk, J, Kench, Jg, Grimison, P, Cooper, Cl, Sandroussi, C, Goodwin, A, Mead, Rs, Tucker, K, Andrews, L, Texler, M, Forest, C, Epari, Kp, Ballal, M, Fletcher, Dr, Mukhedkar, S, Zeps, N, Beilin, M, Feeney, K, Nguyen, Nq, Ruszkiewicz, Ar, Worthley, C, Chen, J, Brooke-Smith, Me, Papangelis, V, Clouston, Ad, Barbour, Ap, O'Rourke, Tj, Fawcett, Jw, Slater, K, Hatzifotis, M, Hodgkinson, P, Nikfarjam, M, Eshleman, Jr, Hruban, Rh, Wolfgang, Cl, Lawlor, Rt, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Biankin, Av, Dixon, J, Jamieson, Nb, and Chang, Dk
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Drug Resistance ,General Physics and Astronomy ,02 engineering and technology ,Mice ,Cancer-Associated Fibroblasts ,Cell Movement ,lcsh:Science ,Inbred BALB C ,Cancer ,education.field_of_study ,Mice, Inbred BALB C ,Multidisciplinary ,Tumor ,021001 nanoscience & nanotechnology ,3. Good health ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,0210 nano-technology ,Pancreas ,Signal Transduction ,Cancer microenvironment ,Cell biology ,Science ,Population ,Perlecan ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cell Line ,03 medical and health sciences ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Humans ,Animals ,Neoplasm Invasiveness ,education ,Cell Proliferation ,Neoplastic ,fungi ,General Chemistry ,Immunotherapy ,medicine.disease ,Pancreatic Neoplasms ,030104 developmental biology ,Gene Expression Regulation ,Drug Resistance, Neoplasm ,Cancer cell ,Cancer research ,biology.protein ,Neoplasm ,lcsh:Q ,Stromal Cells ,Tumor Suppressor Protein p53 ,Heparan Sulfate Proteoglycans - 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., Subtypes of cancer associated fibroblasts can both promote and suppress tumorigenesis. Here, the authors investigate how p53 status in pancreatic cancer cells affects their interaction with cancer associated fibroblasts, and report perlecan as a mediator of the pro-metastatic environment.
- Published
- 2019