Thursday, May 15, 2025
5/15/2025
T helper cells and stem cells in colon homeostasis and tumor initiation - Project Summary Intestinal neoplasia originates in stem cells that render their function niche-independent, or non-stem cells that acquire stem-cell traits. We recently discovered a novel upper crypt intestinal stem cell (ISC) population marked by Fgfbp1 in the small intestine. Our findings define a novel lineage hierarchy of the intestinal epithelium and are in contrast to the widely-accepted model that Lgr5+ crypt base columnar cells in the crypt bottoms are the sole ISCs during homeostasis. Our preliminary data suggest that Fgfbp1 marks bona fide colon stem cells (CSCs). The role of chronic inflammation in intestinal neoplasia has long been established, but remains poorly understood. T cell immunity is particularly important in intestinal neoplasia, with data in mice and humans showing that certain T helper cell types and cytokines promote versus protect against neoplasia and early carcinogenesis. Here, we propose to investigate the role of T helper cells on the fate of CSCs and on colon neoplasia from the perspective of Fgfbp1+ as the marker for CSCs. Here we hypothesize that the Fgfbp1+ CSCs are cells-of-origin of colon neoplasia both via the conventional adenoma pathway and the serrated pathway, thus giving rise to distinct subtypes of tumors. We further postulate that T helper cells and cytokines modulate ISC self-renewal and differentiation during homeostasis, and dysregulation of these processes contribute to neoplasia. Our proposal examines these hypotheses through the following Aims: 1. Determine whether T cell cytokines modulate Fgfbp1+ CSC function during colon epithelial regeneration during homeostasis. 2. Determine whether Fgfbp1+ CSCs function as cells-of-origin of neoplasia via conventional pathway mutational events, and whether T cell cytokines modulate tumor initiation and progression. 3. Determine whether Fgfbp1+ CSCs function as cells-of-origin of neoplasia via non-conventional serrated pathway mutational events, and whether T cell cytokines modulate tumor initiation and progression. Completion of our studies will unveil new insights into mechanisms of immune interactions with epithelial stem cells in the early initiating events of tumorigenesis. These studies will have impact on new translational approaches spanning from prevention to molecular pathology/diagnostics and therapeutics.
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