Bhattacharjee, Sonakshi and Hamberger, Florian and Ravichandra, Aashreya and Miller, Maximilian and Nair, Ajay and Affo, Silvia and Filliol, Aveline and Chin, LiKang and Savage, Thomas M. and Yin, Deqi and Wirsik, Naita Maren and Mehal, Adam and Arpaia, Nicholas and Seki, Ekihiro and Mack, Matthias and Zhu, Di and Sims, Peter A. and Kalluri, Raghu and Stanger, Ben Z. and Olive, Kenneth P. and Schmidt, Thomas and Wells, Rebecca G. and Mederacke, Ingmar and Schwabe, Robert F. (2021) Tumor restriction by type I collagen opposes tumor- promoting effects of cancer-associated fibroblasts. JOURNAL OF CLINICAL INVESTIGATION, 131 (11): e146987. ISSN 0021-9738, 1558-8238
Full text not available from this repository. (Request a copy)Abstract
Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these potentially opposing functions by interrogating functional relationships among CAF subtypes, their mediators, desmoplasia, and tumor growth in a wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented the main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis but not in nondesmoplastic metastatic tumors. Single-cell RNA-Seq in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell-depleted and HSC-selective knockout mice, uncovered direct CAF-tumor interactions as a tumor-promoting mechanism, mediated by myofibroblastic CAF-secreted (myCAF-secreted) hyaluronan and inflammatory CAF-secreted (iCAF-secreted) HGF. These effects were opposed by myCAF-expressed type I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type I collagen may convert CAF from tumor promoting to tumor restricting.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LIVER; FIBROSIS; METASTASIS; STIFFNESS; RESECTION; FORCE; CELLS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Nephrologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Sep 2022 08:32 |
| Last Modified: | 27 Sep 2022 08:32 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48027 |
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