Mathematical Biology Seminar Rob Judson-Torres, U of U School of Medicine Wednesday, February 28, 2024 1:45pm in LCB 222 Title: The genomic evolution of phenomic instability in cancer Abstract: Phenomic instability is a feature of increased phenotypic plasticity that permits cancer cells to swiftly adapt to environmental stressors. The genetic alternations that unlock phenomic instability during cancer evolution are unknown. We identified that loss of CDKN2A, one of the most common genetic alterations across human cancers, accelerates the rates of phenotypic switching and cellular adaptability. Inhibition of phenomic instability was p16INK4A-dependent, yet distinct from the protein’s established role suppressing cellular proliferation. We uncover inosine monophosphate dehydrogenase (IMPDH), an enzyme critical in nucleotide biosynthesis, as a novel partner of p16INK4A. In human cancer models, p16INK4A expression inhibited of nascent transcription, and diminished cellular adaptability to environmental pressures. Our findings identify phenomic instability as a genetically evolved trait during tumor progression and suggest pharmacological targeting of this mechanism may offer a new avenue for reducing the emergence rate of therapeutic resistance.