Grant Abstract: A Major Nutritional Effect on Intestinal Stem Cells and Tumors

Grant Number: 5R01CA214625-04
PI Name: Augenlicht
Project Title: A Major Nutritional Effect on Intestinal Stem Cells and Tumors

Abstract: Our published and unpublished data demonstrate that the nutritional environment is fundamental in determining how and which intestinal epithelial cell populations function as stem cells in both homeostasis and tumorigenesis in the intestinal mucosa. In this regard, our data and that of others establish that lower vitamin D3 levels reprogram Lgr5hi crypt base columnar cells and lower their accumulation of mutations, suppressing their function as stem cells in homeostasis and tumorigenesis. In compensation, Bmi1+ cells are at least one alternate population recruited to function as stem-like/progenitor cells to maintain the mucosa and become capable of tumor initiation. However, the Bmi1+ cell progeny are highly heterogeneous. Therefore, major new issues raised by these data are identification of the sub-set of Bmi1+ derived cells that assume these new progenitor cell functions and dissection of the mechanisms by which the cells are mobilized. Preliminary data from single cell RNAseq experiments generate the hypothesis that fine-tuning of Notch signaling by post-translational modification of Notch receptors in a rare population of Bmi1+ derived cells permits: a) these rare cells to be poised as multi-lineage precursors; b) that it is these cells that are then mobilized to compensate for the loss of Lgr5hi stem cell function. This application is for supplemental funding to RO1 CA R01CA214625, “A Major Nutritional Effect on Intestinal Stem Cells and Tumors“ to use the powerful method of single cell RNAseq, now routine in our lab, and unique genetic models, to: 1) determine how vitamin D3 level in a rodent purified diet determines the representation of these rare cells in the mucosa as well as shifts in overall lineage allocation; 2) identify the genes and pathways that drive these shifts in response to vitamin D3 levels; 3) genetically inactivate either Pofut1 or lunatic fringe, key post-translational modifiers of Notch receptor signaling that fine-tune Notch activity in normal development, to determine the role of each in fine-tuning Notch signaling to: i) poise the rare cells as multi-lineage precursors; i) mediate their recruitment in response to lower vitamin D3. These data are fundamental for: 1) understanding mechanisms establishing relative risk for intestinal cancer; 2) identification of markers of risk for early evaluation; 3) design of more effective strategies for dietary intervention to modulate risk.

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