Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts
Sonakshi Bhattacharjee, … , Ingmar Mederacke, Robert F. Schwabe
Sonakshi Bhattacharjee, … , Ingmar Mederacke, Robert F. Schwabe
Published April 27, 2021
Citation Information: J Clin Invest. 2021;131(11):e146987. https://doi.org/10.1172/JCI146987.
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Research Article Hepatology Oncology

Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts

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.

Authors

Sonakshi Bhattacharjee, Florian Hamberger, Aashreya Ravichandra, Maximilian Miller, Ajay Nair, Silvia Affo, Aveline Filliol, LiKang Chin, Thomas M. Savage, Deqi Yin, Naita Maren Wirsik, Adam Mehal, Nicholas Arpaia, Ekihiro Seki, Matthias Mack, Di Zhu, Peter A. Sims, Raghu Kalluri, Ben Z. Stanger, Kenneth P. Olive, Thomas Schmidt, Rebecca G. Wells, Ingmar Mederacke, Robert F. Schwabe

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Figure 13

Hgf promotes tumor cell proliferation through Met receptor.

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Hgf promotes tumor cell proliferation through Met receptor. (A) Represen...
(A) Representative IHC images and quantification of Ki67+ cells in Pan02 and CMT93 models in Hgffl/fl and HgfΔHSC animals (n = 10–15 per group). Scale bars: 100 μm. (B) Pan02 cells treated with recombinant mouse HGF (25 ng/ml) or vehicle for 10 minutes followed by a phospho-kinase array and Western blot for phosphorylated and total ERK1/2 and AKT. (C) Pan02 cells treated with HGF (25 ng/ml) or Merestinib (3 mM) or U0126 (10 mM) and followed by recombinant mouse HGF (25 ng/ml) or vehicle for 48 hours followed by Ki67 staining. Scale bars: 250 μm. Statistics were done using Mann Whitney U test or unpaired t test dependent on data distribution (A) or 1-way ANOVA with Kruskal Wallis post hoc test (C). Data are shown as the mean ± SEM.