Abstract C035: Altered developmental programming of intestinal stem cells in a maternal obesogenic environment as a risk factor for EO-CRC

Abstract Colorectal cancer (CRC) is the third most prevalent cancer worldwide and rising in incidence and mortality among younger populations. The molecular mechanisms and targetable prevention strategies for early-onset CRC remain unknown. No primary risk factor is yet attributed to early-onset CRC, however, evidence suggests that the adoption of a Western diet is a substantial contributor. Therefore, we tested whether a maternal pro-obesity high-fat Western diet (HFD) leads to offspring’s early risk of neoplastic transformation in mouse models. We find that offspring exposed to a maternal HFD during pre- and postnatal development until weaning have increased adenomas later in life, with altered intestinal stem cell and tissue programs into adulthood: increased stem cell numbers, proliferation, regenerative capacity, hypermetabolism, and lineage bias towards secretory cells. Moreover, we find that extrinsic cues from the immune system are highly involved in this early-epithelial patterning and further demonstrate using in vitro mouse and human organoid models that pro-inflammatory cytokine IL-17a can exert many of these early persistent features. Stable maternal HFD-induced programs are established early during critical developmental stages as post-weaning administration of anti-IL-17a antibodies are insufficient to block the stem cell and tissue phenotypes. Our studies suggest that altered epithelia-immune co-patterning is a risk for early-onset CRC and view IL-17a as a potential dominant driver of maladaptive homeostasis that may accelerate disease. Because the establishment of epithelial-immune relationship in early life influences interactions that potentiate pathological disorders later in life, our continued work will shed light on how early exposure to obesogenic conditions influences offspring’s health and risk of early onset tumorigenesis. Citation Format: Miyeko D. Mana. Altered developmental programming of intestinal stem cells in a maternal obesogenic environment as a risk factor for EO-CRC abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr C035.