Molecular Imaging Core Summary The one shared resource core of the Acquired Resistance to Therapy and Iron (ARTI) Center is the Molecular Imaging Core (MIC). The MIC is a build out of the Molecular Imaging Laboratory (MIL), a central facility within the Department of Cancer Systems Imaging at The University of Texas MD Anderson Cancer Center that has received support from The Radiation Oncology and Cancer Imaging Program (ROCIP) under the Cancer Center Grant (P30CA016672). For more than two decades, the MIL has been an expert hub for preclinical imaging, including positron emission tomography (PET) and bioluminescence imaging, and has already established national and international collaborations and distributed key plasmids, cell lines, and reporter animals to the global scientific community. The virtual MIC will support the central theme of the ARTI Center, which is to determine whether ferroptosis plays a major role in acquired resistance to radiation therapy (RT). The MIC will implement and manage the precise, preclinical imaging support infrastructure (personnel, reagents, animals, software, and customized hardware resources) for the three research projects. The MIC will collaborate with ARTI Center investigators in developing preclinical imaging protocols and analyses with appropriate biological and biochemical controls, robust test-retest analysis, and imaging statistical support when appropriate (Aim 1). In Aim 2, the MIC will provide timely access to unique plasmid-based reporters, reporter animals, PET reagents, and fluorescent biosensors, while leveraging MIL and MD Anderson cores’ expertise to modify reagents when appropriate to meet ARTI Center needs. Regarding workflow, the MIC will provide timely service, training, access to customized macro- and microscopic imaging systems, premium image analytics, and custom imaging analysis to ARTI Center investigators (Aim 3). For Project 1, the MIC will perform noninvasive bioluminescence imaging in preclinical small animal models of lung and esophageal cancer to test the effects of ferroptosis inducers (FINs) combined with RT as well as FINs combined with immunotherapy in overcoming acquired tumor RT resistance. To help determine whether hypoxia modulates ferroptosis and acquired RT resistance in Project 2, the MIC will perform bioluminescence imaging to monitor hypoxic tumor growth resistance in response to RT and the potential radiosensitizing effects of FINs, hypoxia-inducible factor (HIF) and activating transcription factor 4 (ATF4) inhibitors or knockdown, and hyperbaric oxygen therapy as well as to identify hypoxic regions within tumors. With Project 3, the MIC will assess the role of myeloid cell expansion in conferring ferroptosis resistance to chemoradiation therapy using preclinical tumor models derived from esophageal adenocarcinoma patients and using a novel PET tracer developed by the MIC. The MIC will also serve as a resource for not only ARTI Center investigators, but also for o...