CCL5 and GLUT1 define leader cells in collective invasion of colorectal cancer

Abstract Background Many solid tumors rely heavily on the regulation and organization of leader and follower cells during the collective invasion. However, leader cells’ specific biomarkers and mechanisms in colorectal cancer (CRC) collective invasion are unclear. This study aimed to identify the specific biomarkers of leader cells and reveals their molecular mechanisms during CRC collective invasion and metastasis. Methods The 3D photoconvertible CRC spheroid model in vitro was constructed to isolate leader cells and follower cells. The RNA-Seq, functional, and animal experiments revealed that GLUT1, PLOD2, and CCL5 in leader cells were required for CRC collective invasion. Results CCL5 up-regulated the expression of GLUT1 and PLOD2 through PI3K/Akt signaling in leader cells. Moreover, GLUT1 and CCL5 could be used as specific biomarkers for leader cells in CRC collective invasion, and their co-expression was associated with poor prognosis of CRC patients. Notably, blocking GLUT1 and CCL5-CCR5 effectively inhibited CRC collective invasion. Conclusions Our findings illustrate that CCL5 and GLUT1 may define leader cells and are required for CRC collective invasion as a potential key regulator of hypoxia-induced metabolic shifts and collagen deposition.