Title : Cortactin suppresses mTOR-dependent senescence in circulating tumor cells
Abstract:
Tumor senescence is a critical mechanism underlying metastatic progression and recurrence. How pre-metastatic circulating tumor cells (CTCs) explore senescence for maintaining survival in the blood stream is unclear. Using patient-derived melanoma CTC lines and animal explant (CDX) models, we identified an unexpected role for the cytoskeletal regulator cortactin (CTTN) in mTOR/p53-dependent senescence. Cortactin localized to Rab7-positive endosomes and maintained late-endosomal homeostasis. Its depletion induced aberrant endosomal aggregates with mTOR accumulation and overactivation, subsequently leading to p53 activation, G0/G1 arrest, and cellular senescence. This oncogene-induced senescence (OIS) is characterized by SASP upregulation, SA-β-gal formation, loss of Ki-67 and Lamin B1, and elevated mitochondrial ROS (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 were significantly correlated with therapeutic resistance and disease progression in a prospective cohort of melanoma patients. We thus uncovered a unique senescent CTC subpopulation regulated by the “Cortactin–mTOR–p53–mtROS” axis. A sequential “One-two punch” strategy using cortactin depletion followed by anti-Bcl-xL senolytics was devised to eliminate these persistent CTCs and suppress blood-borne metastasis.
Key words: Cortactin; Circulating Tumor Cells; Senescence; Metastatic dormancy; mTOR; Late endosome.
