A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy

Cancer cells disseminate from primary tumors and seed in distant organs, where they can remain dormant for many years before forming clinically detectable metastases. Little is known about how extracellular matrix (ECM) sensing and remodeling can induce and sustain dormancy of disseminated tumor cells (DTCs). Another unanswered question is whether dormant cells themselves are able to assemble ECM niches to sustain their phenotype. From an analysis of the ECM proteome, we found that dormant cancer cells assemble an ECM niche enriched in type III collagen. Tumor-derived, but not stroma-derived type III collagen is required to sustain tumor dormancy as its disruption restores proliferation of dormant cancer cells. Mechanistically, we show that type III collagen interacts with DDR1 to activate STAT1 signaling to induce and maintain dormancy. Second harmonic generation two-photon microscopy further reveals that the dormancy-to-reactivation transition is accompanied by changes in collagen three-dimensional architecture and type III collagen abundance. In vivo, exogenous type III collagen stops tumor growth by inducing dormancy and prevents reawakening of residual dormant cells by prolonging their quiescence. Analysis of clinical samples reveals that type III collagen levels are increased in tumors from head and neck squamous cell carcinoma (HNSCC) lymph node negative patients when compared lymph node positive patients. Our data reveal a novel mechanism by which dormant DTCs depend on the assembly of a type III collagen-rich ECM niche to maintain quiescence. Manipulation of these mechanisms could serve as a self-sustained barrier to metastasis through DTCs dormancy induction.