Stiff, solid microenvironments induce Chromosome loss and challenge Epigenetic therapies

ABSTRACT: This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT- CA-24-029. Our proposed projectfacilitates a new collaboration and introduces Asst Professor Karmella Haynes as a newInvestigator to NCI and its PSON Program. Our parent award U01-CA254886 has begun yr-4 and

focuses on solid tumors and genetic instability through development of novel fluorescent `ChReporters'. These enable us to image and track the first induction of chromosome loss and propagation into colonies. This is expected to decrease the levels of Tumor Suppressors (e.g. p53, PTEN, APC, etc.), which is understudied in

these contexts and is the focus of our efforts. The Haynes lab brings deep expertise in epigenetics including regulation of Tumor Suppressor genes, which are a major challenge in cancer, because loss of these key factors is a major modern challenge to rescue (and lagging behind successes in inhibition of Oncogenes). Solid tumors

exhibit more chromosome losses and gains than liquid tumors, and clinical efforts with epigenetic drugs that possibly rescue Tumor Suppressor levels to some extent are showing better efficacy in Liquid tumors. All of this motivates our studies of chromosome loss using our ChReporters in Solid Tumor models to address how such

drugs as well as molecularly specific CRISPR approaches affect Tumor Suppressor levels and cancer-related phenotypes.