Influence of developmental programming in adult stem cells and cancer

Maternal obesity is epidemiologically linked to offspring's risk of colorectal cancer (CRC), the third most prevalent cancer worldwide. In the United States, nearly half the women of childbearing age are obese or overweight with the trend likely to continue to rise. Along with alarming levels of obesity is the increasing incidence and mortality rate of CRC in younger populations, suggesting very early exposure may result in later development and progression of tumorigenesis. To develop meaningful preventative interventions, the underlying molecular details impacting offspring's risk need to be addressed. Our goal is to determine the impact of maternal obesity on the transformative risk in offspring by directly assessing the developmental programming of intestinal stem cells (ISCs), the cell-of-origin for many intestinal cancers, during pre and postnatal growth. Our aims are predicated on our previous studies from adult mice maintained on a pro-obesity high-fat Western diet (HFD) in which we determined an increases stem cell numbers, proliferation, regenerative capacity, and ability to accelerate tumorigenesis. These features are governed by PPAR-delta or PPAR-alpha, two nuclear receptors orchestrating multiple aspects of lipid metabolism. We established that the metabolic-transcriptional PPAR axis is necessary to enhance stemness and tumorigenic potential, and also stabilize the enhanced HFD-induced ISC chromatin state by epigenetic adaptations. We anticipate a similar program occurs in ISCs from mice exposed to maternal obesity. We posit that naïve exposure to an obesogenic maternal environment establishes a pro-tumorigenic ground state in offspring's intestinal stem cells. Using genetically engineered mouse and organoid models, our objective is to distinguish ISC developmental programming and determine both early intrinsic adaptations and extrinsic environmental interactions that promote establishment of a stable pre-pathological ISC ground state. Our aims are to: (1) interrogate the effects and durability of a pro-obesity maternal diet on offspring's colonic stem cell state; (2) test the requirement and sufficiency of intrinsic lipid mediators in ISC homeostasis and risk of later tumorigenesis; (3) test the contribution of external inflammatory signaling during ISC developmental programming and persistent tumor risk. Elucidating offspring's tumorigenic risk distinctly in ISCs established during maternal dependence is necessary to ascertain how the ISC environment contributes to intestinal homeostasis and long-term disease risk. This proposal will advance our nascent understanding of the developmental programming in early life that leads to health and disease disparities in later life.