Cancer-Secreted Exosomal HSPC111 Promotes Colorectal Cancer Liver Metastasis By Reprogramming Lipid Metabolism in Cancer-Associated Fibroblasts

Abstract Background: Metastasis and metabolic deregulation are two of the major hallmarks of cancer. Recent studies have revealed the critical driving role of metabolic reprogramming of tumor cells to promote colorectal cancer (CRC) metastasis. However, little is known about the metabolic alterations of cancer-associated fibroblasts (CAFs) in the pre-metastatic niche and how these changes facilitate CRC metastasis.Methods: Liquid chromatography-mass spectrometry (LC-MS) and Isobaric Tags for Relative and Absolute Quantitation (i-TRAQ) method were performed to identify the comparative metabolites and proteins expression in CAFs treated with exosomes derived from CRC cells, respectively. Tissue Microarray (TMA) was used to evaluate the level of HSPC111 in patient’s primary CRC tissues with or without liver metastasis. Co-immunoprecipitation (Co-IP), RNA-seq, chromatin immunoprecipitation (ChIP) migration and wound healing assay and immunofluorescence staining were employed to explore the expression regulation mechanism of exosomal HSPC111 in CAFs. Xenograft models were used to determine whether exosomal HSPC111 can remolding pre-metastatic niche of CAFs to promote CRC liver metastasis (CRLM) in vivo.Results: Here, we demonstrate that CRC cell-secreted exosomal HSPC111 induces a lipid metabolism reprogramming process in CAFs. Importantly, our results indicate that CRC patients with liver metastasis had significantly high level of HSPC111 in CRC tissues than CRC patients without liver metastasis. Mechanistically, HSPC111 upregulate the level of acetyl-CoA and histone acetylation by phosphorylating of ATP-citrate lyase (ACLY) in CAFs. This lipid metabolism reprogramming in CAFs facilitates CXCL5 secretion in vitro and pre-metastatic niche formation in the liver to promote CRLM in an exosomal HSPC111-dependent manner in vivo. In addition, conditioned medium (CM) from CAFs induce EMT of CRC cells by down-regulating E-cadherin levels and up-regulating Vimentin and Snail levels, which could be abolished by CXCL5-neutralizing antibody and CXCR2 inhibitor navarixin. Moreover, the HSPC111-ACLY association in CAFs was reinforced by CXCL5-CXCR2 axis, further promoting exosomal HSPC111 secretion from CRC cells to form a feedforward regulatory loop.Conclusion: Our present study reveals a novel insight into the pro-metastatic role of lipid metabolism reprogramming in CAFs and suggests the CXCL5-CXCR2 axis may be a promising target for halting CRLM.