CCL2/CCR2 axis promotes perineural invasion of salivary adenoid cystic carcinoma via ITGβ5-mediated nerve-tumor interaction

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2025-01, Vol.1871 (1), p.167484, Article 167484
• Main Authors: Yang, Zihui, Li, Huan, Wang, Jun, Gao, Wanpeng, Zhao, Qi, Meng, Qingzhe, Huang, Junhong, Xi, Qi, Wei, Jianhua, Yang, Xinjie
• Format: Article
• Language: English
• Subjects: Animals; Carcinoma, Adenoid Cystic - metabolism; Carcinoma, Adenoid Cystic - pathology; CCL2; CCR2; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Coculture Techniques; Exosomes; Exosomes - metabolism; Female; Ganglia, Spinal - metabolism; Ganglia, Spinal - pathology; Humans; ITGβ5; Male; Mice; Mice, Nude; Neoplasm Invasiveness; Perineural invasion; Receptors, CCR2 - genetics; Receptors, CCR2 - metabolism; Salivary adenoid cystic carcinoma; Salivary Gland Neoplasms - genetics; Salivary Gland Neoplasms - metabolism; Salivary Gland Neoplasms - pathology
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167484

Perineural invasion (PNI) is a notorious feature of salivary adenoid cystic carcinoma (SACC) and other neurotropic tumors. The pathogenesis of PNI that involves the molecular communication between the tumor and the suffered nerve is elusive. The in vitro co-culture assays of SACC cells with dorsal root ganglia (DRG) or neural cells showed that nerve-derived CCL2 activated CCR2 expression in SACC cells, promoting the proliferation, adhesion, migration, and invasion of SACC cells via the ERK1/2/ITGβ5 pathway. Meanwhile, SACC-derived exosomes delivered ITGβ5 to promote the neurite outgrowth of neural cells or DRG. Blocking of CCL2/CCR2 axis or ITGβ5 inhibited the PNI of SACC cells in models in vitro by 3D co-culture of DRG with SACC cells and in vivo by xenografting SACC cells onto the murine sciatic nerve. High levels of ITGβ5 in tissues or plasma exosomes were significantly correlated with CCL2 and CCR2 expression in the tissues and associated with PNI and poor prognosis of SACC cases. Our findings revealed a novel reciprocal loop between neural and tumor cells driven by the CCL2/CCR2 axis and exosomal ITGβ5 during PNI of SACC. The present study may provide a prospective diagnostic and anti-PNI treatment strategy for SACC patients via targeting the nerve-tumor interactions. [Display omitted] •Nerve-derived CCL2 induces malignant behavior of SACC cells via CCR2/ERK1/2/ITGβ5.•SACC-derived exosoms carries ITGβ5, and promotes neurite outgrowth towards tumor.•Blocking of CCL2/CCR2 or ITGβ5 inhibits the PNI of SACC cells in vitro and in vivo.•High level of ITGβ5 in plasma exosomes predicts PNI and poor prognosis in SACC cases.