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

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.

SUBMITTER: Zhang C

PROVIDER: S-EPMC8758774 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer.

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Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-06-30 | GSE106923 | GEO

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Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer (RNA-Seq)

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