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Cancer-derived exosomal HSPC111 promotes colorectal cancer liver metastasis by reprogramming lipid metabolism in cancer-associated fibroblasts

Chong ZhangDepartment of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaXiang-Yu WangDepartment of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaPeng ZhangDepartment of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaTao-Chen HeDepartment of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaJia-Hao HanDepartment of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaRui ZhangDepartment of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaJing LinDepartment of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaJie FanDepartment of Pathology, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaLu LuDepartment of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaWen-Wei ZhuDepartment of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaHu-Liang JiaDepartment of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaJu-Bo ZhangDepartment of Infectious Diseases, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, ChinaJin-Hong ChenDepartment of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, China. [email protected]

2022en

ABI

Annotatsiya

Tumor metastasis is a hallmark of cancer. The communication between cancer-derived exosomes and stroma plays an irreplaceable role in facilitating pre-metastatic niche formation and cancer metastasis. However, the mechanisms underlying exosome-mediated pre-metastatic niche formation during colorectal cancer (CRC) liver metastasis remain incompletely understood. Here we identified HSPC111 was the leading upregulated gene in hepatic stellate cells (HSCs) incubated with CRC cell-derived exosomes. In xenograft mouse model, CRC cell-derived exosomal HSPC111 facilitated pre-metastatic niche formation and CRC liver metastases (CRLM). Consistently, CRC patients with liver metastasis had higher level of HSPC111 in serum exosomes, primary tumors and cancer-associated fibroblasts (CAFs) in liver metastasis than those without. Mechanistically, HSPC111 altered lipid metabolism of CAFs by phosphorylating ATP-citrate lyase (ACLY), which upregulated the level of acetyl-CoA. The accumulation of acetyl-CoA further promoted CXCL5 expression and secretion by increasing H3K27 acetylation in CAFs. Moreover, CXCL5-CXCR2 axis reinforced exosomal HSPC111 excretion from CRC cells and promoted liver metastasis. These results uncovered that CRC cell-derived exosomal HSPC111 promotes pre-metastatic niche formation and CRLM via reprogramming lipid metabolism in CAFs, and implicate HSPC111 may be a potential therapeutic target for preventing CRLM.

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Identifikatorlar

DOI: 10.1038/s41419-022-04506-4

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