Project Details
Description
Western-style diets are strongly linked to human sporadic colorectal cancer (CRC), the predominant
subtype of all human CRCs. This can be recapitulated in the mouse fed a purified rodent diet (NWD1)
mimicking intake of major human nutrient risk factors for CRC. Our extensive published work on this
model has established that there are fundamental biochemical and molecular field effects in the
histologically normal appearing mucosa of NWD1 fed mice, long before sporadic tumors develop. This
includes altered epithelial cell maturation, expanded and elevated Wnt signaling throughout the mucosa,
and altered energy metabolism.
More recently, we reported that feeding NWD1 has profound effects on ability of Lgr5hi crypt base
columnar cells to function as stem cells in intestinal homeostasis and in tumor development. Data
submitted for publication (presented herein), establish that feeding NWD1 differentially programs Lgr5hi
and Bmi1creERT2 marked intestinal stem cells (RNAseq analysis). In Lgr5hi cells, this significantly elevates
expression of DNA damage response (DDR) genes, in particular in the mismatch repair pathway,
suppresses accumulation of Lgr5hi cell somatic mutations, and alters mutational spectra and signature.
Further, consistent with the shift we reported in relative utilization of carbohydrate and fat as energy
sources in mice fed NWD1, there was reduced expression in Lgr5hi cells of genes encoding components
of the TCA cycle and of multiple subunits for each of the 5 complexes of mitochondrial electron transport,
and for Pgc1a, a master regulator of mitochondrial function and biogenesis. As a consequence, NWD1
reduced Lg5hi cell function in intestinal homeostasis and tumorigenesis, but increased ability of Bmi1
progeny to act as stem-like cells in homeostasis and tumor development. Therefore, NWD1 - highly
relevant to human nutritional exposures strongly linked to population risk for CRC – had a major impact
on sculpting the contribution of different intestinal stem cell populations to contribute to mucosal
homeostasis and tumorigenesis. These dietary effects on adult stem cells are potentially paradigm
shifting in terms of understanding risk for sporadic tumors. Our overall hypothesis is that these changes
in long-lived stem cells provide new approaches for early evaluation and modulation of relative risk.
Aim 1 identifies the evolution with time of epigenetic and genetic alterations by which NWD1 alters
mouse intestinal/colonic adult stem cells in elevating probability for sporadic CRC, and the relative
stability of such changes once established when the diet is altered. Aim 2 determines the impact of
NWD1 on altered DNA damage response to promoting tumorigenesis from the different stem cell
populations. Aim 3 determines the extent to which genetic inactivation of Pgc1a targeted to Lgr5 stem
cells of the intestinal and colonic mucosa is sufficient to recapitulate the effects of NWD1 on alteration of
Lgr5 stem cell programming and contribution of Lgr5 cells to intestinal homeostasis and tumorigenesis.
Status | Finished |
---|---|
Effective start/end date | 7/5/18 → 5/31/23 |
Funding
- National Cancer Institute: $278,826.00
- National Cancer Institute: $214,412.00
- National Cancer Institute: $478,440.00
- National Cancer Institute: $483,374.00
- National Cancer Institute: $493,238.00
- National Cancer Institute: $493,238.00
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