Julie Di Martino : "Cancer dormancy: an ECM perspective"

Metastasis is the primary cause of death in cancer patients. However, metastasis occur years after primary tumor removal. This delay is a consequence of tumor dormancy, a reversible growth arrest that can be regulated by the interaction of disseminated tumor cells with the microenvironments. Extracellular matrix (ECM) is a key component of the microenvironment that provide signals to the tumor cells and regulates tumor progression. Here, we investigate the role of tumor-derived ECM and tumor cell/ECM interactions in dormancy. Methods. We used dormancy models of human head and neck squamous cell carcinoma as well as murine mammary carcinoma coupled with multiphoton intravital imaging and ECM-enriched proteomic to define how dormant cells secrete type III collagen to sustain their quiescence. Results. SHG imaging showed that ECM of dormant cells is mainly formed of a curly ECM whereas proliferative tumors set up collagen fibers straight. Transcriptome and proteome analysis of dormant and proliferative tumors revealed that dormant ECMs are highly enriched in collagens. Interestingly, depleting COL3A1 in dormant cells results in their awakening and restoration of tumor growth in vivo. We identified DDR1, a collagen receptor for these collagens, as upregulated in dormant cells upon dormancy onset (i.e hypoxia). DDR1 downregulation leads to the reactivation of dormant cells in vivo. ECM-proteomic analysis revealed that DDR1 is required to sustain tumor cell-derived COL3A1 expression in dormant cell suggesting that DDR1 sustain dormancy by regulating the assembly of a pro-dormant ECM enriched in type III collagen. Moreover, we further identify a transcription factor network activated downstream DDR1, involving STAT1, that contribute to dormancy of cancer cells and to the assembly of this tumor self-made pro-quiescence ECM. Conclusion. We demonstrated that upregulation of DDR1 prime cancer cells to secrete and assemble a type III collagen enriched pro-quiescence ECM through STAT1 signaling.