| Title: |
CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan |
| Authors: |
Vennin, C; Mélénec, 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; 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; Christ, Daniel; Cox, Thomas; Timpson, Paul; Phillips, Phoebe; Whitelock, John; Pajic, Marina; Gill, Anthony; Croucher, David |
| Source: |
urn:ISSN:2041-1723 ; Nature Communications, 10, 1, 3637 |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2019 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
3101 Biochemistry and Cell Biology; 32 Biomedical and Clinical Sciences; 31 Biological Sciences; 3204 Immunology; 3211 Oncology and Carcinogenesis; Cancer; Rare Diseases; Pancreatic Cancer; Digestive Diseases; 2.1 Biological and endogenous factors; Animals; Cancer-Associated Fibroblasts; Cell Line; Tumor; Cell Movement; Cell Proliferation; Drug Resistance; Neoplasm; Gene Expression Regulation; Neoplastic; Heparan Sulfate Proteoglycans; Mice; Inbred BALB C; Neoplasm Invasiveness; Pancreas; Pancreatic Neoplasms; Signal Transduction; Tumor Suppressor Protein p53; Australian Pancreatic Genome Initiative (APGI); anzsrc-for: 3101 Biochemistry and Cell Biology |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://hdl.handle.net/1959.4/unsworks_61438 |
| DOI: |
10.1038/s41467-019-10968-6 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_61438; https://unsworks.unsw.edu.au/bitstreams/47a5bd77-37b0-4828-a7bd-ad959c2d5978/download; https://doi.org/10.1038/s41467-019-10968-6 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY ; https://creativecommons.org/licenses/by/4.0/ ; free_to_read |
| Accession Number: |
edsbas.D38B8EF4 |
| Database: |
BASE |