Engulfment and cell motility protein 1 fosters functional reprogramming of tumor-associated macrophages in colorectal cancer

Abstract Background Functional reprogramming of tumor-associated macrophages (TAMs) is crucial to their potent tumor-supportive capacity. However, the molecular mechanism behind the reprogramming process remains poorly understood. This work aimed to investigate the involvement of engulfment and cell motility protein 1 (ELMO1) in TAM reprogramming in colorectal cancer (CRC).Methods The expression of ELMO1 in CRC was determined by western blots and immunohistochemistry. The biological effects of ELMO1 on TAM reprogramming were evaluated in vitro. The dependence of these effects on Rac1 was assessed using a Rac1 inhibitor (NSC23766). Cell function assays were performed to determine the role of ELMO1-reprogrammed macrophages in the context of CRC progression.Results The expression of ELMO1 in stromal but not epithelial tumor cells was positively associated with advanced clinical stage and poor disease-free survival in CRC. An increase in ELMO1 expression was specifically found in TAMs, but not in other multiple non-malignant stromal cells. Gain- and loss-of-function assays indicated ELMO1 reprogrammed macrophages to a TAM-like phenotype via Rac1 activation. In turn, ELMO1-reprogrammed macrophages were shown to not only facilitate the malignant behaviors of CRC cells but exhibited potent phagocytosis of tumor cells.Conclusion ELMO1 was shown to be a crucial player for TAM reprogramming in CRC. Our work underscores the importance of ELMO1 in determining functional reprogramming of TAMs and may provide new insights on potential therapeutic strategies against CRC.