Yang Yoon Mee, Kim Jieun, Wang Zhijun, Kim Jina, Kim So Yeon, Cho Gyu Jeong, Lee Jee Hyung, Kim Sun Myoung, Tsuchiya Takashi, Matsuda Michitaka, Pandyarajan Vijay, Pandol Stephen J, Lewis Michael S, Gangi Alexandra, Noble Paul W, Jiang Dianhua, Merchant Akil, Posadas Edwin M, Bhowmick Neil A, Lu Shelly C, You Sungyong, Xu Alexander M, Seki Ekihiro
Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Department of Pharmacy.
J Clin Invest. 2025 Feb 13;135(7):e180802. doi: 10.1172/JCI180802.
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.
脂肪变性的肝脏会促进结直肠癌（CRC）的肝转移，但这一过程尚未完全明确。高脂饮食诱导的脂肪变性肝脏会增加癌症相关成纤维细胞（CAF）浸润以及胶原蛋白和透明质酸（HA）的产生。我们使用Has2ΔHSC小鼠（其中Has2在肝星状细胞中被敲除）研究了HA合酶2（HAS2）在脂肪变性肝脏纤维化肿瘤微环境中的作用。Has2ΔHSC小鼠MC38 CRC细胞的脂肪变性肝脏相关转移性肿瘤生长、胶原蛋白和HA沉积以及CAF和M2巨噬细胞浸润均减少。我们发现低分子量HA激活癌细胞中的Yes相关蛋白（YAP），然后YAP释放结缔组织生长因子以进一步激活CAF来表达HAS2。单细胞分析揭示了CAF衍生的HAS2与M2巨噬细胞和CRC细胞之间通过CD44建立的联系；这些细胞通过程序性死亡配体1和程序性细胞死亡蛋白1（PD - 1）与耗竭的CD8 + T细胞相关。HA合成抑制剂减少了CRC的脂肪变性肝脏相关转移、YAP表达以及CAF和M2巨噬细胞浸润，并改善了对抗PD - 1抗体的反应。总之，脂肪变性肝脏通过CAF与转移性肿瘤之间的双向调节来调节纤维化肿瘤微环境，以增强转移性癌症活性，从而增强CRC在肝脏中的转移潜力。
