Christopher S. McGinnis, PhD, Postdoctoral Fellow Stanford University Cancer metastasis is the cause of death for ~90% of patients with solid tumors, partly because effective anti-metastatic therapies are severely lacking. The immune system is thought to represent the ‘Achilles heel’ of metastatic progression because tumor-mediated immune reprogramming is both necessary for metastasis and represents a key vulnerability due to the plasticity of immune phenotypes. Despite this potential, anti-metastatic immunotherapies have yet to be developed due to fundamental limitations in high-throughput screening strategies. In this proposal, Dr. McGinnis describes the development of a single-cell RNA-seq (scRNA-seq) coupled chemical compound screening platform that has the potential to discover anti-metastatic immunotherapies. Leveraging the polyomavirus middle T antigen (PyMT) mouse model in which primary breast tumors and lung metastases form rapidly, robustly, and in the presence of an intact immune system, he first describes experiments which outline biological and technical benchmarks for PyMT lung organotypic slice cultures (OSCs). OSCs represent an ideal in vitro system for discovering anti-metastatic immunotherapies as they can be produced in an arrayed format for sample-multiplexed scRNA-seq while retaining the immune, stromal, and tumor cells present in their in vivo source. He then proposes a data-driven, literature-supported list of candidate compounds, which will be assessed for anti-metastatic effects, subjected to dose-response validation, and then administered in vivo to PyMT mice for functional assays and to determine whether treatment increases metastasis-free survival. Beyond having the potential to discover anti-metastatic immunotherapies, high-throughput immunomodulation studies represent a top-down approach for uncovering novel mechanisms of pro-metastatic, tumor-mediated immune reprogramming. Projects and Grants Interrogating Immunomodulation for Anti-Metastatic Therapy Stanford University | All Cancers | 2022 | Ansuman Satpathy, M.D., Ph.D.
