Inflammation awakens dormant cancer cells by modulating epithelial-mesenchymal phenotypic state [scRNA-Seq]

The awakening of dormant disseminated cancer cells is responsible for the clinical relapses of patients whose primary tumors have been cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, non-proliferative phenotypic state. The awakening of these cells does not occur because of a cancer cell-autonomous process. Instead, inflammation and wound-healing of the surrounding tissue microenvironment causes them to shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire stemness and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their stemness, doing so without ongoing heterotypic signaling from the lung microenvironment. EGFR ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is essential for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse. Overall design: For the samples of day3 or day7 control, Sum159 ITGB4 low clone 1 cells were injected into the lungs of mice through tail vein. At day 6 or day 10, lungs were harvested and dissociated into single cell suspension and sent for scRNA sequencing. For the samples of day 3 or day 7 bleomycin, Sum159 ITGB4 low clone 1 cells were injected into the lungs of mice through tail vein. 3 days later, mice were administrated with bleomycin by intratracheal instillation. After 3 days or 7 days of bleomycin administration, lungs were harvested and dissociated into single cell suspension and sent for scRNA sequencing.