Tumor-derived type IX collagen regulates dormancy in triple-negative breast cancer cells.

Metastasis and recurrence of triple-negative breast cancer (TNBC), are mainly attributed to the presence of dormant cancer cells (DCCs), yet the molecular mechanisms governing the maintenance and reactivation of DCC dormancy remain poorly elucidated. This study identified collagen IX alpha 1 chain (Col9a1) as a gene specifically expressed in TNBC dormant cells and confirmed that it is a key molecule sustaining DCC dormancy. Mechanistic studies revealed that COL9A1 sustains TNBC cell dormancy by suppressing the FAK-AKT-p27 signaling axis, thereby inducing G0/G1 cell cycle arrest. Col9a1 knockdown reactivates DCCs, and the reactivated cells recruit natural killer (NK) cells by upregulating retinoic acid early inducible 1γ (RAE-1γ) and secreting proinflammatory cytokines (IL-15/IL-18), thus abrogating the immune evasion capacity of DCCs and enhancing the chemosensitivity of reactivated TNBC cells to docetaxel. This study uncovers a novel mechanism by which COL9A1 regulates TNBC cell dormancy, indicating that COL9A1 can serve as a potential biomarker for assessing the dormant phenotype of TNBC and predicting tumor recurrence, as well as a novel therapeutic target for TNBC. This study also provides preclinical evidence for developing COL9A1-targeted combination therapies for TNBC.