Commensal dysbiosis promotes the development of colorectal cancer liver metastasis via the CCL6/CCR1 axis

Abstract

Purpose: Gut microorganisms are involved in the occurrence and progression of various cancer types, including colorectal cancer. Several studies have indicated that the destruction of commensal homeostasis can promote tumor metastasis. The purpose of our study was to clarify the effect of gut commensal dysbiosis on the risk of liver metastasis of colorectal cancer (CRLM) and its mechanisms. Methods: We established a mouse model of CRLM with a background of commensal dysbiosis. Using this model, we studied the impact of commensal dysbiosis on CRLM. Results: Commensal dysbiosis promotes the development of CRLM via the C-C chemokine ligand 6 (CCL6) and the C-C chemokine receptor 1 (CCR1) axis. It was found that commensal dysbiosis altered the tumor microenvironment (TME) of the liver by recruiting tumor-associated macrophages (TAMs), notably M-2-like TAMs and promoted the growth of liver metastasis. The effect of promoting liver metastasis was achieved by upregulating the expression levels of CCL6 to drive CCR1+TAMs infiltration into the TME. It is important to note that inhibition of CCR1 expression can reduce CRLM. Conclusion: Commensal dysbiosis could promotes the development of CRLM via CCL6/CCR1 signaling and represent an approach to prevent CRLM. The results of the current research study suggested that targeting this axis could be an effective method to inhibit the CRLM by regulating the TME.