Exploring Nucleophagy and Inflammation in the Tumor Microenvironment

Nuclear stress and inflammation are intimately tied in tumorigenesis and cancer cell survival. Here, I explore immune environments across various types of cancers and nucleophagy, a mechanism by which cancer cells respond to nuclear stress. Nucleophagy, a selective form of autophagy, is an intracellular catabolic process involved in the degradation of nuclear material. A mechanistic understanding of nucleophagy remains limited due to a lack of chemical or genetic regulators that can modulate the process. I describe a high content drug screen that identifies a panel of drugs that bi-directionally regulate autophagy marker MAP1LC3B nuclear localization in a renal cancer cell line. I investigate the effects of two hit compounds from the screen on the degradation of nuclear envelope protein Lamin B1 under normal and nuclear stress conditions. Novel chemical tools from the screen allow for deeper exploration of the players involved in nucleophagy. Nuclear envelope degradation in cancer cells is often accompanied by DNA damage and chromatin rearrangement, which leads to inflammation in the tumor microenvironment (TME). Though the contribution of immune infiltration on cancer prognosis is widely recognized, a precise characterization of the immune environment across different tumors and tumor states remains incomplete. The recent advent of immunotherapy for pediatric cancers calls for a better understanding of immune cell interactions in the TME. Here, I analyze controlled-access whole transcriptomic and exome sequencing datasets to map the immune landscape of pediatric kidney cancers, specifically Wilms tumors. This analysis is the first precise characterization of the immune environment for pediatric kidney cancers. Investigating the immune landscape may offer predictive insight into pediatric cancer prognosis and immunotherapy response as well as guide future personalized medicine approaches