Talk Title:

Systems analysis of ligand effects induced by chromosomal instability on the tumor ecosystem

Abstract:

 Multicellular programs underly emergent phenotypes in health and disease. Yet, deciphering higher-order functional interactions amongst cell types remains a major challenge. Cell-to-cell communication often takes the form of ligands emanating from “donor” cells to receptors expressed on “target” cells. Complimentary ligand-receptor pairs are well annotated, and their co-occurrence can be used to identify putative interactions from single cell data. However, no methods exist to quantify cellular responses to ligand-receptor-mediated interactions in the microenvironment. Thus, we developed ContactTracing – a fundamentally new, systems level approach that exploits inter- and intra-sample variability to infer ligand effects on gene expression in target (receptor-expressing) cells without prior knowledge of downstream signaling. Foundational work towards benchmarking and validation of this method was performed in isogenic breast cancer models distinguished by tumor cell-intrinsic rates of chromosome missegregation (a cellular process called chromosomal instability, or CIN). Through this, we identified tumor ligands emanating from an endoplasmic reticulum (ER)-stress response as potential mediators of immune suppression in chromosomally unstable tumors. Indeed, CIN-induced chronic STING activation led to rapid interferon-selective desensitization and a switch to ER-stress-dependent transcription. Moreover, inhibition of chronic STING – or key mediators of its unfolded protein response to ER-stress – suppressed metastasis in syngeneic models of melanoma, breast and colorectal cancer; validating this innovative methodology and identifying a critical mediator of cancer progression.