The alterations caused by obese extracellular vesicles on colorectal cancer tumor microenvironment

Project Summary Colorectal cancer (CRC) patients with a high body-mas index (BMI) have poor efficacy to chemotherapy, creating an urgent need to design targeted therapy for this group of cancer patients. During obesity, the excess visceral adipose tissue (AT) deposited around major organs in the abdomen triggers systemic metabolic dysregulation

and creates an environment conducive to cancer development, particularly colorectal cancer (CRC). Obese AT secretes more extracellular vesicles (EVs) compared to non-obese AT, which can be taken up by distant tissues. EVs are lipid-membraned vesicles that carry cargo from the parent cell and are important for inter-organ

communication. Unbiased proteomic analysis revealed that obese EVs (OB-EVs) and non-obese (N-OB) EVs are distinctly different in terms of their cargo, with an enrichment of the glycolytic enzyme triose phosphate isomerase 1 (TPI1) in OB-EVs. Consequently, OB-EV treatment of CRC cells resulted in higher TPI1 levels

compared to N-OB EV treatment. Functionally, OB-EVs increased basal glycolysis of human and mouse CRC cells and enhanced the ability of CRC cells to form 3D tumoroids and spheroids. CRC cells can aberrantly increase glycolysis to support tumor growth and aggressive, however, it is not known whether these pro-

tumorigenic effects can get enhanced during obesity. In the F99 portion of this grant, I will determine if the cargo from AT-derived EVs is utilized by CRC cells to change their metabolism and promote a pro-tumorigenic phenotype, and whether it is enhanced during obesity. I will use a novel mouse model of intestinal tumorigenesis lacking EV secretion from adipocytes that will be

challenged with obesity to elucidate the role of OB-EV cargo in CRC development. The goals of this project are to 1) confirm whether OB-EVs transfer TPI1 to CRC cells and its regulation on glycolysis and 2) determine the oncogenic role of OB-EV and TPI1 in CRC development in vivo. The results from this study will help advance

the field of EV biology in cancer during obesity and identify potential targets for cancer therapeutics in obese CRC patients. In the K00 portion of this grant, I will expand on elucidating the impact of AT-derived EVs on the immune population of CRC TME. Obese CRC TME is known to be immunosuppressive with increased infiltration of M2-

like macrophages. However, there is a lack of studies enumerating the underlying molecular players mediating the observed phenotype. Therefore, I propose to determine whether OB-EVs reprogram macrophages in the obese TME to an immunosuppressive M2-like phenotype to promote tumor progression. I will seek K00 labs with

comprehensive expertise on tumor immunology and associated signaling pathway to provide me with the training I require to complete my project and characterize the impact of obesity in CRC TME.