Single Cell Analysis Unveils the Role of the Tumor Immune Microenvironment and Notch Signaling in Dormant Minimal Residual Disease

Understanding the complex ecosystem that promotes dormant cell survival and elucidating those factors that eventually overcome growth constraints and result in proliferation may provide new insights and help identify novel strategies to prolong dormancy and prevent recurrence. To dissect the molecular pathways and the microenvironments involved in regulation of tumor dormancy, we utilized a novel immunocompetent transgenic model to study residual disease, dormancy, and relapse. We discovered 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. Additionally, the Jagged-1/Notch signaling pathway was shown to regulate many aspects of tumorigenesis including stem cell development, epithelial-mesenchymal transition, and immune cell homeostasis during dormancy. An anti-Jagged-1 inhibitory antibody prolonged dormancy and delayed tumor recurrence due to the pleotropic effects of inhibiting the Jagged-1/Notch signaling pathway both in the tumor cells and the microenvironment. Overall design: Single-cell RNA-seq profiles of tumors from 4 stages: Primary, dormant, long-term dormant, and recurrent, and 2 treatment arms (control and anti-Jagged-1) were generated by deep sequencing using 10x Genomics Chromium System.