Cortactin Suppresses mTOR-Dependent Senescence in Circulating Tumor Cells

Abstract Tumor senescence is a critical mechanism underlying tumor progression and recurrence. A better understanding of how pre-metastatic circulating tumor cells (CTCs) exploit senescence to survive in the blood stream 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 (OIS) was characterized by 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 melanoma patients. 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 metastatic progression of melanoma.