Cortactin Suppresses mTOR-Dependent Senescence in Circulating Tumor Cells

Tumor senescence is a critical mechanism underlying tumor progression and recurrence. A better understanding of how premetastatic circulating tumor cells (CTC) exploit senescence to survive in the bloodstream could help reveal vulnerabilities for therapeutic intervention. Using patient-derived melanoma CTC lines and xenograft models, we identified a role for the cytoskeletal regulator cortactin in mTOR/p53-dependent senescence. Cortactin localized to Rab7-positive endosomes and maintained late-endosomal homeostasis. Depletion of cortactin induced aberrant endosomal aggregates with mTOR accumulation and hyperactivation, subsequently leading to p53 activation, G0-G1 arrest, and cellular senescence. This oncogene-induced senescence was characterized by the induction of the senescence-associated secretory phenotype and β-galactosidase (SA-β-gal), loss of Ki-67 and lamin B1, and elevated mitochondrial reactive oxygen species (mtROS). Notably, a positive feedback loop between p53 and mtROS was essential for maintaining stable senescence in CTCs. Clinically, the proportion of SA-β-gal-positive senescent CTCs was significantly correlated with therapeutic resistance and disease progression in a prospective cohort of patients with melanoma. A sequential strategy using cortactin depletion followed by an anti-Bcl-xL senolytic eliminated the persistent CTCs and suppressed blood-borne metastasis. Thus, this study uncovered a unique senescent CTC subpopulation regulated by a cortactin/mTOR/p53/mtROS axis that can be targeted to suppress the metastatic progression of melanoma. SIGNIFICANCE: The cytoskeleton regulator cortactin governs senescence induction and maintenance in melanoma circulating tumor cells, providing an axis that can be targeted by a sequential therapeutic strategy to block metastasis.