ABSTRACT, Tumor Microenvironment and Metastasis (TMM) Research Program The Tumor Microenvironment and Metastasis (TMM) Research Program is a highly interactive basic science Program in which members combine fundamental research expertise to understand the biology of cancer cell autonomous effects in relation to paracrine actions and specific components of the tumor microenvironment (TME) and metastasis. Understanding factors released by the TME into systemic circulation will provide novel diagnostic strategies, whereas understanding how the TME nurtures cancer cells to enhance metastasis and its clinical consequence will lead to new cancer treatment strategies. The TMM overarching goal is to understand the pathobiology of solid tumors, the TME, and systemic effects of metastases and develop our discoveries into novel cancer targets and therapies. We advance this vision by focusing on two central themes with four aims. Theme 1 pertains to tumor-stromal cell and immune cell interactions in the tumor micro- and macroenvironments. Aim 1 is to identify pathways, mechanisms, and molecular targets alongside model development within the tumor microenvironment that impact tumor cell survival; Aim 2 is to understand systemic consequences of tumor, metastases, and treatment in the macroenvironment of the host including tumor effects on muscle wasting and bone loss. Theme 2 pertains to tumor development and progression and molecular mechanisms of metastases. Aim 3 is to identify pathways, mechanisms, and molecular targets involved in tumor progression and metastasis; Aim 4 is to investigate molecular mechanisms of metastasis through bioengineering, genetically engineered mouse models, and targeted therapies. In the past five years, notable successes with funded projects, including renewal of the SPORE in hyperactive Ras signaling, a project in a new Epigenetic Therapies SPORE, a new U01 in stromal reprogramming in pancreatic cancer, and further development of working groups in cancers relevant to our catchment, resulted in increased funding in these areas. New team grants were also submitted including two SPORE applications and recruitment into musculoskeletal effects of cancer metastasis group. Pilot project RFAs expanded inter- and intra-programmatic collaborations, resulting in new grants. Annual retreats fostered focused and robust collaborations, and we hosted visiting experts and recruited faculty members with expertise based on needs identified at the retreats. The TMM Program has 35 Full and 24 Associate Members, from 17 Departments and five Schools on the campuses of Indiana University (IU) School of Medicine, IU-Purdue University Indianapolis, and IU School of Medicine-Bloomington. The Program has $12.4M in total direct funding (up 36% since 2018) and $10.8M in peer-reviewed funding (up 59%), with $2.8M from the NCI (up 17%) and $4.8M (up 167%) from other NIH institutes. In the current grant period, TMM members authored 583 publications (23% intra-...