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

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 hierarch...

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Published in:Nature communications Vol. 10; no. 1; pp. 3637 - 22
Main Authors: Vennin, Claire, Mélénec, Pauline, Rouet, Romain, Nobis, Max, Cazet, Aurélie S., Murphy, Kendelle J., Herrmann, David, Reed, Daniel A., Lucas, Morghan C., Warren, Sean C., Elgundi, Zehra, Pinese, Mark, Kalna, Gabriella, Roden, Daniel, Samuel, Monisha, Zaratzian, Anaiis, Grey, Shane T., Da Silva, Andrew, Leung, Wilfred, Mathivanan, Suresh, Wang, Yingxiao, Braithwaite, Anthony W., Christ, Daniel, Benda, Ales, Parkin, Ashleigh, Phillips, Phoebe A., Whitelock, John M., Gill, Anthony J., Sansom, Owen J., Croucher, David R., Parker, Benjamin L., Pajic, Marina, Morton, Jennifer P., Cox, Thomas R., Timpson, Paul
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 12.08.2019
Nature Publishing Group
Nature Portfolio
Subjects:
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14/69
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Animals
Cancer
Cancer-Associated Fibroblasts - pathology
Cell Line, Tumor
Cell Movement
Cell Proliferation
Chemotherapy
Drug Resistance, Neoplasm - genetics
Fibroblasts
Gene Expression Regulation, Neoplastic - genetics
Heparan Sulfate Proteoglycans - metabolism
Humanities and Social Sciences
Metastases
Metastasis
Mice
Mice, Inbred BALB C
multidisciplinary
Neoplasm Invasiveness - pathology
p53 Protein
Pancreas - pathology
Pancreatic cancer
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Perlecan
Science
Science (multidisciplinary)
Signal Transduction - physiology
Stroma
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-019-10968-6