Tumor dormancy is a stage in which
residual cancer cells remain inactive, but regrowth of dormant
cancer cells contributes to recurrence. The complex ecosystem in
cancer that promotes cell survival and the factors that eventually overcome growth constraints and result in proliferation remain to be fully elucidated. Doing so may provide new insights and help identify novel strategies to prolong
cancer dormancy and prevent disease recurrence. To dissect the molecular pathways and the microenvironments involved in regulation of dormancy, we utilized a novel immunocompetent transgenic model to study
minimal residual disease and relapse. This model revealed a significant reorganization of
cancer cell structures, stroma, and immune cells, with
cancer cells showing dormant cell signatures. Single-cell
RNA sequencing uncovered remodeling of myeloid and lymphoid compartments. In addition, the
Jagged-1/Notch signaling pathway was shown to regulate many aspects of
tumorigenesis, including stem cell development, epithelial-to-mesenchymal transition, and immune cell homeostasis during
minimal residual disease. Treatment with an anti-Jagged-1 antibody inhibited the
Jagged-1/Notch signaling pathway in
tumor cells and the microenvironment, delaying
tumor recurrence. These findings uncover a cascade of regulatory changes in the microenvironment during dormancy and identify a therapeutic strategy to undercut these changes.
SIGNIFICANCE: Single-cell
RNA-sequencing analysis reveals dormancy-associated changes in immune and stromal cells and demonstrates a rationale to pursue
Jagged-1/Notch pathway inhibition as a viable therapeutic strategy to reduce disease recurrence.