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

Vennin, C. et al. (2019) CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. Nature Communications, 10, 3637. (doi: 10.1038/s41467-019-10968-6) (PMID:31406163) (PMCID:PMC6691013)

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.

• Item Type: Articles
• Additional Information: Biankin, A.V., Dixon, J., Jamieson, N.B., and Chang, D.K. are members of the Australian Pancreatice Genome Initiative (APGI).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jamieson, Professor Nigel and Biankin, Professor Andrew and Dixon, Miss Judith and Kalna, Dr Gabriela and Morton, Professor Jen and Chang, Professor David and Sansom, Professor Owen
• Authors: Vennin, C., Mélénec, P., Rouet, R., Nobis, M., Cazet, A. S., Murphy, K. J., Herrmann, D., Reed, D. A., Lucas, M. C., Warren, S. C., Elgundi, Z., Pinese, M., Kalna, G., Roden, D., Samuel, M., Zaratzian, A., Grey, S. T., Da Silva, A., Leung, W., Mathivanan, S., Wang, Y., Braithwaite, A. W., Christ, D., Benda, A., Parkin, A., Phillips, P. A., Whitelock, J. M., Gill, A. J., Sansom, O. J., Croucher, D. R., Parker, B. L., Pajic, M., Morton, J. P., Cox, T. R., Timpson, P., Biankin, A. V., Dixon, J., Jamieson, N. B., and Chang, D. K.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Nature Communications 10: 3637
• Publisher Policy: Reproduced under a Creative Commons License