ABSTRACT/SUMMARY (Overall) The overall goal of this Program is to investigate the role of the Integrated Stress Response (ISR) signaling pathway in tumor cell fate and tumor progression. Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established vascularity of the tissue. The ISR integrates signals from sensors (such as the endoplasmic reticulum kinase PERK and cytoplasmic kinase GCN2) of cellular nutrients to homeostatic processes including translational control, carbon and oxygen metabolism and receptor signaling. The ISR has also been shown to facilitate oncogene-mediated tumor progression, suggesting that it may also respond to bioenergetic challenges triggered by aberrant oncogene-dependent signaling. The overall hypothesis to be tested in the proposed studies is that the Integrated Stress Response plays a pivotal role in mediating MYC-dependent and hypoxia-dependent tumor progression through its capacity to engage and regulate key pathways involved in circadian, translational, metabolic and immune functions thereby facilitating tumor cell survival and growth. The above hypothesis will be tested by three highly integrated projects: Project 1 will define miRNAs subject to ISR control whose function is to fine-tune protein synthesis during an ISR/UPR response. Two key, microRNAs, miR-211 and miR-217, are the focus; collectively, they function as regulators of Bmal1 during ER stress and their contribution to Bmal1 repression to lymphoma progression is critical for tumorigenesis. Project 2 will identify critical nodes in metabolism and translation control which are coordinately regulated by both ATF4 and c-MYC and delineate the mechanism of co-regulation of common transcriptional targets. It will also functionally test the role of ATF4 in MYC-dependent transformation and tumorigenesis. Project 3 will delineate the mechanisms underlying ISR-induced IFNAR1-dependent and independent inactivation of the IFN1 pathway, its role in the loss of viability of intratumoral cytotoxic lymphocytes and the generation of the immune privileged niches. It will also determine whether targeting these mechanisms can augment anti-cancer immunity. All three projects will make extensive use of Core A (Administrative) and scientific Cores B (Metabolomics/Genomics) and C (Biostatistics) and have already established a working, highly collaborative relationship. Collectively, our three integrated and synergistic Projects will provide a molecular framework that addresses the potential efficacy of targeting the ISR to antagonize malignancy in three highly prevalent and lethal types of tumors.