2026 Theses Doctoral

Nutrigenomic underpinnings of HMGCS2-dependent metabolic inflammation and aberrant stem-cell state in colorectal cancer

Ho, Jennifer P.

Colorectal cancer is a leading cause of cancer-related death, with rising incidence among individuals under 50 years of age – a demographic shift strongly associated with Western dietary patterns. While diet-related inflammation has been linked to early-onset colorectal cancer (EO-CRC), the metabolic and cellular mediators through which dietary exposures promote tumor-permissive stem cell states remain poorly.

This dissertation investigated the nutrigenomic underpinnings through which dietary metabolic stress shapes aberrant stem-cell fate and tumor progression in colorectal cancer, using EO-CRC as a tractable model for interrogating diet-associated tumorigenesis. Through integrated analysis of human transcriptomic datasets and mechanistic studies from mouse models, I identified HMGCS2, the rate-limiting enzyme in colonic ketogenesis, as a diet-responsive metabolic control point linking nutrient availability to aberrant stem-cell states. HMGCS2 is selectively suppressed in tumor-resident stem cells from left-sided EO-CRC and marks a patient subset with poor clinical outcomes. Loss of colonic HMGCS2 in mice recapitulates key features of EO-CRC, including distal-predominant tumorigenesis and accelerated tumor initiation through engagement of Rho/ROCK-dependent aberrant stem-cell states.

These states drive stage-dependent cellular reorganization, transitioning from proliferative tumor-initiating populations to coordinated wound-healing niches that sustain progression through secretory activity. Dietary exposures suppress colonic HMGCS2 to establish metabolic stress and engage aberrant stem-cell states, while dysbiosis amplify inflammatory signaling to reinforce niche activity particularly during tumor progression.

This work establishes that colonic HMGCS2 deficiency operates as a diet-responsive metabolic control point that translate nutritional inputs into aberrant stem-cell state changes, revealing a nutrigenomic mechanism linking diet to tumor susceptibility. The finding that metabolic stress can engage injury-associated regenerative programs without experimentally induced tissue injury reveals a previously unrecognized mode of stem cell state transition with implications for understanding diet-associated epithelial malignancies. The responsiveness of these states to environmental modulation and their dependence on targetable signaling pathways positions metabolic control points as intervention targets for diet-driven tumorigenesis, offering a framework for precision prevention strategies upstream of irreversible genetic change.