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

  • Cell Death Dis. 2022 Jan 13;13(1):57. doi: 10.1038/s41419-022-04506-4.
Chong Zhang   #  1  2 ,  Xiang-Yu Wang   #  1  2 ,  Peng Zhang   #  1  2 ,  Tao-Chen He  1  2 ,  Jia-Hao Han  1  2 ,  Rui Zhang  1  2 ,  Jing Lin  1  2 ,  Jie Fan  3 ,  Lu Lu  1  2 ,  Wen-Wei Zhu  1  2 ,  Hu-Liang Jia  1  2 ,  Ju-Bo Zhang  4 ,  Jin-Hong Chen  5  6
Affiliations
  • 1. Department of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, China.
  • 2. Institute of Cancer Metastasis, Fudan University, Shanghai, China.
  • 3. Department of Pathology, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, China.
  • 4. Department of Infectious Diseases, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, China.
  • 5. Department of General Surgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road (M), Shanghai, 200040, China. [email protected].
  • 6. Institute of Cancer Metastasis, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 35027547 DOI: 10.1038/s41419-022-04506-4
Abstract

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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