Department of Gastrointestinal Surgery, Central Hospital of Shaoyang, Shaoyang, China.
Department of Colorectal Surgery and Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Cancer Sci. 2023 Feb;114(2):410-422. doi: 10.1111/cas.15628. Epub 2022 Dec 7.
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. Here, we identify engulfment and cell motility protein 1 (ELMO1) as a crucial player for TAM reprogramming in colorectal cancer (CRC). 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 nonmalignant stromal cells. Gain- and loss-of-function assays indicated ELMO1 reprogrammed macrophages to a TAM-like phenotype through 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. Taken together, our work underscores the importance of ELMO1 in determining functional reprogramming of TAMs and could provide new insights on potential therapeutic strategies against CRC.
肿瘤相关巨噬细胞（TAMs）的功能重编程对于其强大的肿瘤支持能力至关重要。然而，重编程过程背后的分子机制仍知之甚少。在这里，我们确定吞噬和细胞迁移蛋白 1（ELMO1）是结直肠癌（CRC）中 TAM 重编程的关键因素。ELMO1 在基质细胞而非上皮肿瘤细胞中的表达与 CRC 的晚期临床阶段和不良无病生存率呈正相关。ELMO1 表达的增加仅在 TAMs 中发现，而在其他多种非恶性基质细胞中未发现。增益和缺失功能实验表明，ELMO1 通过 Rac1 激活将巨噬细胞重编程为类似于 TAM 的表型。反过来，ELMO1 重编程的巨噬细胞不仅促进 CRC 细胞的恶性行为，而且还表现出对肿瘤细胞的有效吞噬作用。总之，我们的工作强调了 ELMO1 在决定 TAMs 的功能重编程中的重要性，并为针对 CRC 的潜在治疗策略提供了新的见解。
