Tumor Microenvironment and Metastasis Program

TUMOR MICROENVIRONMENT AND METASTASIS PROGRAM - PROJECT SUMMARY/ABSTRACT The Tumor Microenvironment and Metastasis (TMM) Program is focused on investigating the genetic, epigenetic, biochemical, microenvironmental, and developmental pathways that drive dissemination, dormancy, and recurrence. These studies will identify novel therapeutic targets and biomarkers to address each of these stages of metastatic progression. The overall goal of TMM is to catalyze basic research on the mechanisms by which cancer cell intrinsic and microenvironmental signals conspire to fuel cancer cell systemic dissemination, persistence during dormancy, and metastatic outgrowth in target organs. The overarching hypothesis is that detailed mechanistic studies of both the tumor cell and the microenvironment during dissemination from primary sites, re-dissemination from metastatic foci, dormancy and stem programs in collaboration with the Stem Cell and Cancer Biology Program, and metastatic recurrence will lead to the identification and characterization of novel therapeutic targets in collaboration with Cancer Therapeutics Program and biomarkers that may be useful for personalizing the treatment of metastatic disease. Importantly, understanding target organ biology and how it relates to individual’s predispositions to disease, lifestyle, and aging (in collaboration with Cancer Epidemiology Prevention and Control Program) will provide insights into management of metastatic cancer. TMM investigators utilize the power of basic science and an array of model systems (e.g., zebrafish, mice, organoids), imaging modalities (e.g., intravital imaging, multiplex immunofluorescence), and human studies (e.g., tissue analyses, epidemiological data) to characterize key aspects of how cancer cells, together with the immune and non-immune microenvironment, control mechanisms of: (i) early and late dissemination, (ii) re-dissemination from metastatic foci, (iii) extravasation and residual disease dormancy, and (iv) metastatic cell sensitivity/resistance to systemic therapies (e.g., chemotherapy, targeted agents, immunotherapy) and effect of therapies on the TME. Each of these approaches is explored in multiple cancers relevant to the catchment area, (prostate, breast, HNSCC, melanoma, multiple myeloma). These objectives will be achieved through two specific aims, both fostering intra- and inter-programmatic activities as well as community programs to accelerate TMM’s interdisciplinary, clinical, and educational output to ultimately impact cancer patients represented within our catchment area. TMM’s specific aims are to: (1) Identify tumor microenvironments and signaling networks that fuel dissemination and (2) Discover the target organ-driven mechanisms for cancer cell survival and dormancy and how niche alterations drive metastasis.