CAV2-expressing Nerves induce Metabolic Switch toward Mitochondrial Oxidative Phosphorylation to Promote Cancer Stemness

Cancer cells and the nervous system engage in a dynamic interplay, significantly influencing initiation and progression in head and neck squamous cell carcinoma (HNSCC). Our findings highlight that cancer cells drive an increase in caveolin-2 (Cav2) expression within trigeminal ganglia and associated neural fibers in the tumor milieu, fostering a reciprocal attractant relationship between tumor cells and nerves. Notably, the knockout of Cav2, either globally or specifically in sensory neurons or glial cells, markedly attenuates the growth of orthotopically implanted tongue tumors. Moreover, Cav2-expressing nerves are implicated in shifting cancer cell metabolism towards mitochondrial oxidative phosphorylation, a process involved in maintenance of cancer stem cells (CSCs). Our results also demonstrate that Cav2-expressing nerves confer stemness properties to cancer cells. Disruption of Cav2 expression, both globally and in specific neural cell types, impedes tumorigenesis and progression in a 4-NQO- induced HNSCC mouse model.This interplay observed between cancer cells, neurons, and glial cells suggests a potential mechanism through which tumor-associated nerves might influence cancer stemness via metabolic reprogramming. This highlights a possible new direction for anticancer therapy that warrants further investigation.