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.
Highlights
Colorectal cancer (CRC) is the third most common malignancy and has risen to the second leading cause of cancer-related death worldwide [1]
To compare the abilities of educating hepatic stellate cells (HSCs) into Cancer-associated fibroblasts (CAFs) among the four CRC cell-derived exosomes, the expression of α-SMA and FAP in treated HSCs were evaluated by western blot, which showed most highly in LX-2 cells incubated with HCT116-derived exosomes (ExoHCT116) (Fig. 1B)
QRT-PCR showed that HSPC111 mRNA have no significant change in LX-2 cells incubated with ExoHCT116 compared with control (Fig. 1F), which indicated that the elevated HSPC111 protein in LX-2 cells was delivered by CRC cell-derived exosomes
Summary
Colorectal cancer (CRC) is the third most common malignancy and has risen to the second leading cause of cancer-related death worldwide [1]. Exosomes, ranging from 50–160 nm in diameter, are cancerderived vesicles to participate in pre-metastatic niche formation by deliver tumor products including proteins, nucleic acids and lipid to distant organs, and can transform fibroblasts to CAFs [11, 12]. In our previous study [15], we revealed that CRC cells show specific metabolic reprogramming during the process of liver metastasis. Most studies have focused on the metabolic changes of CAFs resident in the primary tumor [17, 18], and there remains little known about the mechanism of metabolic reprogramming of CAFs in the pre-metastatic niche during the process of CRC liver metastasis. We uncovered the critical role of CRC cell-derived exosomal HSPC111 in facilitating pre-metastatic niche formation by inducing lipid metabolic reprogramming of CAFs in liver. Four weeks after CRC cells injection, mice were euthanized and liver metastasis were
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