As of 2017, 78% of US Veterans are overweight or obese consuming a Western diet characterized by a high intake of saturated fat. It is well-established that obesity is associated with increased risk of developing colorectal cancer, the third most commonly diagnosed cancer in the Veterans Affairs Health Care System. Adipose tissue is the largest endocrine organ producing and secreting extracellular vesicles (EVs) carrying molecular cargo that can be taken up by recipient cells, resulting in intra-organ communication. Our preliminary data suggest that EV secretion is increased from adipose tissue from obese humans and mice. Additionally, obese adipose tissue EVs are enriched with enzymes involved in the fatty acid (FA) metabolic process. Fatty acid β-oxidation (FAO) is a catabolic pathway in the mitochondria crucial for ATP production by oxidative phosphorylation for cancer cell survival and growth. Initiation and progression of colorectal cancer is thought to involve an accumulation of genetic mutations predominantly in Lgr5+ colonic crypt base columnar (CBC) stem cells that confer a clonal advantage and expansion. However, the role of FAO in Lgr5+ CBCs remains unknown and the effect of adipose tissue-derived EVs on mitochondrial metabolism or function of colonic Lgr5+ CBCs has not been studied. Our preliminary data suggest that EVs derived from obese adipose tissue increase persistence of colonic Lgr5+ stem/progenitor function that is dependent on FAO. We also show that obese adipose EV-induced FAO increases β-Catenin transcriptional activation, which is crucially important for CBC stemness and crypt proliferation. EVs derived from adipose tissue of obese mice increase colon tumoroid growth dependent on FAO. We will test the hypothesis that EVs originating in the adipose tissue stimulate distant CBC stem cells, and in obese individuals, favor the progression to CRC. We propose 3 specific aims to test this hypothesis: Aim 1. To determine whether EVs shed from obese adipose tissue contain cargos that alter colonic CBC metabolism, CBC function, and epithelial homeostasis; Aim 2. Define the mechanism whereby obese adipose EVs drive CBC functional changes to enhance tumorigenesis; and Aim 3. Define the anti-tumor response of targeting pathways altered by adipose EVs in CRC. Our long-term goal is to determine whether targeting adipose EV-induced signaling pathways in the colon is an effective therapeutic strategy to combat colorectal cancer during obesity.