Friday, May 9, 2025
5/9/2025
Wnt signaling in obesity-associated colorectal cancer - Project Summary Obesity affects 42% of the U.S. population and is a major risk factor for the development of colorectal cancer. Obese colorectal cancer patients have a five-fold increased risk of death compared to normal weight counterparts. However, the mechanisms by which obesity increases colorectal cancer progression and metastasis are poorly understood, which limits the development of effective prevention and treatment strategies for colorectal cancer in obese individuals. The vast majority of colorectal cancers are initiated by loss of the tumor suppressor gene Apc in colonic stem cells, and subsequent activation of the Wnt signaling pathway. Wnt signaling is also required for maintenance of advanced colorectal cancers and metastases. Research from our group demonstrates that diet-induced obesity markedly upregulates Wnt signaling in intestinal and colonic stem cells by promoting a peroxisome proliferator-activated receptor delta (PPAR-d) transcriptional program, which in turn increases cancer development. These findings suggest that inhibition of Wnt signaling is a highly attractive therapeutic strategy for obesity-associated colorectal cancer. We and others have demonstrated that colon tumors are maintained by Lgr5+ cancer stem cells, and single cell RNA sequencing data from our lab shows that these cells are Wnt-active, while non-cancer stem cells are Wnt-low. However, development of Wnt inhibitors to treat Apc-deficient cancers or to target cancer stem cells has proven elusive. Rac1-GTP, a member of the Rho family of GTPases, is an intracellular transducer that promotes Wnt signaling by mediating nuclear translocation of beta-catenin. Prex1 is a Rac-specific Rho GTPase guanine nucleotide exchange factor that activates Rac1 by facilitating the exchange of GTP to GTP. We found that Prex1 and active Rac1-GTP are highly enriched in intestines and colon cancers of mice treated with high fat diet or an agonist of PPAR-d. Loss of Rac1 signaling markedly reduces intestinal tumor initiation by inhibiting Wnt activation. Our long-term goal is to understand mechanisms of Wnt activation in colorectal cancer and to develop new treatment strategies for this disease. Here, we hypothesize that Prex1-dependent Rac1-GTP activity mediates obesity-induced tumorigenesis by inducing Wnt signaling in Lgr5+ cancer stem cells. In Aim 1, we will determine the role of Prex1 signaling in high fat diet and PPAR-d-mediated intestinal stem cell regeneration and tumor initiation. In Aim 2, we will determine the function of the Prex1 / Rac1-GTP signaling axis in high fat diet and PPAR-d-dependent colorectal cancer stem cell function. In Aim 3, we will identify the role of PPAR-d transcriptional targets in colorectal cancer stem cell function in the setting of diet- induced obesity. The goal of this proposal is to identify mechanisms by which obesity-induced Wnt signaling promotes colorectal cancer progression. Our studies will provide preclinical rationale for clinical trials to test Rac1-GTP inhibitors for the treatment of colorectal cancer, particularly in obese individuals, by inhibiting Wnt signaling.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).