| dc.description.abstract | The increasing prevalence of obesity and its associated risk of colorectal cancer (CRC) reinforces the urgent need to determine the underlying mechanisms contributing to the promotion of CRC in obese individuals. CRC is the second leading cause of cancer-related mortality in the United States, and up to 20% of all cancer-related deaths may be attributed to obesity. An abundance of epidemiological evidence suggests that CRC risk increases proportionally to body-mass index (BMI), predominantly in men. However, the molecular mechanisms by which high-fat diet (HFD)-induced obesity increases tumorigenesis remain to be fully elucidated. Therefore, our overall goal is to define how HFD-induced obesity promotes CRC risk.
We hypothesized that HFD constituents modify plasma membrane composition by contributing to and remodeling phospholipid and cholesterol content. Utilizing quantitative fluorescence microscopy and flow cytometry, we demonstrated that a HFD increases plasma membrane cholesterol and rigidity in colonic stem cells and splenic T cells in mice. Interestingly, in a genetic model of obesity (db/db mouse), we did not observe changes in the order/rigidity of the plasma membrane of colonocytes and splenic T cells. In complementary experiments utilizing super-resolution microscopy, HFD induced changes in membrane rigidity were linked to an increase in LRP6 and EGFR nanoclustering and subsequent downstream signaling.
We subsequently assessed the ability of AdipoRon, an adiponectin mimetic, to attenuate Wnt signaling by reducing plasma membrane cholesterol and membrane rigidity in a CRC mouse model. Attenuation of plasma membrane rigidification by AdipoRon treatment disrupted LRP6 clustering and overall colonic polyp formation in APC mutant mouse model for CRC.
Overall, we have demonstrated that a HFD, but not obesity per se, modulates the biophysical properties of the plasma membrane which promote Wnt and EGFR signaling in colonocytes. AdipoRon can ameliorate oncogenic-APC phenotypes in vitro and in vivo through modification of plasma membrane biophysical properties thereby attenuating Wnt signaling. This reduces the ability of tumor cells to signal effectively even in the presence of oncogenic-APC. These data contribute to the mechanistic understanding of how HFD may alter the plasma membrane to increase CRC risk and how AdipoRon may serve as an orally active plasma membrane therapeutic. | |
