Metastatic tumor growth in steatotic liver is promoted by HAS2-mediated fibrotic tumor microenvironment
Yoon Mee Yang, Jieun Kim, Zhijun Wang, Jina Kim, So Yeon Kim, Gyu Jeong Cho, Jee Hyung Lee, Sun Myoung Kim, Takashi Tsuchiya, Michitaka Matsuda, Vijay Pandyarajan, Stephen J. Pandol, Michael S. Lewis, Alexandra Gangi, Paul W. Noble, Dianhua Jiang, Akil Merchant, Edwin M. Posadas, Neil A. Bhowmick, Shelly C. Lu, Sungyong You, Alexander M. Xu, Ekihiro Seki
Yoon Mee Yang, Jieun Kim, Zhijun Wang, Jina Kim, So Yeon Kim, Gyu Jeong Cho, Jee Hyung Lee, Sun Myoung Kim, Takashi Tsuchiya, Michitaka Matsuda, Vijay Pandyarajan, Stephen J. Pandol, Michael S. Lewis, Alexandra Gangi, Paul W. Noble, Dianhua Jiang, Akil Merchant, Edwin M. Posadas, Neil A. Bhowmick, Shelly C. Lu, Sungyong You, Alexander M. Xu, Ekihiro Seki
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Research Article Hepatology Oncology

Metastatic tumor growth in steatotic liver is promoted by HAS2-mediated fibrotic tumor microenvironment

Abstract

Steatotic liver enhances liver metastasis of colorectal cancer (CRC), but this process is not fully understood. Steatotic liver induced by a high-fat diet increases cancer-associated fibroblast (CAF) infiltration and collagen and hyaluronic acid (HA) production. We investigated the role of HA synthase 2 (HAS2) in the fibrotic tumor microenvironment in steatotic liver using Has2ΔHSC mice, in which Has2 is deleted from hepatic stellate cells. Has2ΔHSC mice had reduced steatotic liver–associated metastatic tumor growth of MC38 CRC cells, collagen and HA deposition, and CAF and M2 macrophage infiltration. We found that low–molecular weight HA activates Yes-associated protein (YAP) in cancer cells, which then releases connective tissue growth factor to further activate CAFs for HAS2 expression. Single-cell analyses revealed a link between CAF-derived HAS2 and M2 macrophages and CRC cells through CD44; these cells were associated with exhausted CD8+ T cells via programmed death–ligand 1 and programmed cell death protein 1 (PD-1). HA synthesis inhibitors reduced steatotic liver–associated metastasis of CRC, YAP expression, and CAF and M2 macrophage infiltration, and improved response to anti–PD-1 antibody. In conclusion, steatotic liver modulates a fibrotic tumor microenvironment to enhance metastatic cancer activity through a bidirectional regulation between CAFs and metastatic tumors, enhancing the metastatic potential of CRC in the liver.

Authors

Yoon Mee Yang, Jieun Kim, Zhijun Wang, Jina Kim, So Yeon Kim, Gyu Jeong Cho, Jee Hyung Lee, Sun Myoung Kim, Takashi Tsuchiya, Michitaka Matsuda, Vijay Pandyarajan, Stephen J. Pandol, Michael S. Lewis, Alexandra Gangi, Paul W. Noble, Dianhua Jiang, Akil Merchant, Edwin M. Posadas, Neil A. Bhowmick, Shelly C. Lu, Sungyong You, Alexander M. Xu, Ekihiro Seki

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Figure 5

CAF-derived HAS2 and cancer-derived YAP contribute to a prometastatic immune TME in steatotic liver.

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CAF-derived HAS2 and cancer-derived YAP contribute to a prometastatic im...
(A and B) Representative immunohistochemistry images for F4/80 (A) and CD206 (B) from tumors in Figure 2. Scale bars: 200 μm. (C) Quantification of F4/80-positive (top) and CD206-positive (bottom) areas. (n = 5–7 per group.) Data are presented as mean ± SEM. Statistical significance was calculated with 1-way ANOVA followed by Tukey’s post hoc test. *P < 0.05, **P < 0.01. (D) Tumor-infiltrating CAF and immune cell populations. Uniform manifold approximation and projection (UMAP) of single-cell RNA-Seq from 46,577 cells showing 25 clusters determined by integrated analysis, colored by cluster. Cells were from metastatic liver tumors of LFD-fed and HFD-fed mice. (n = 3 per group.) (E, J, and M) The proportion of CAF (E), M1 and M2 (J), and T cell (M) clusters in metastatic liver tumors of LFD-fed and HFD-fed mice. (F and G) Expression of Has1, Has2, Has3, and Cd44 genes (columns) by specific CAF subpopulations (rows). Dot size represents the cell fraction within the CAF subpopulations. Fill color indicates average expression (Ave. exp.). (H and I) CellChat (53) receptor-ligand analysis of the predicted intercellular communication networks for cells from metastatic liver tumors of LFD-fed and HFD-fed mice. Arrows are proportional to the interaction strength between CAF2 and other cell clusters; node size indicates the number of cells within that population. (K and L) Expression of Cd44 and Cd274 genes (columns) by specific M2 subpopulations (rows). Dot size represents the cell fraction within the M2 subpopulations. (N and O) Expression of key immunomodulatory genes (columns) by specific T cell subpopulations (rows). (P) Proposed model representing cancer YAP regulation of HSC-derived HAS2 for the immunosuppressive TME in steatotic liver.