Mouse genetic models of Lynch syndrome (LS)/defective MMR (dMMR) driven tumorigenesis produce small intestinal tumors. However, long-standing collaborative work of the Co-PIs has now developed a new mouse model that causes LS/dMMR tumorigenesis in the mouse colon by integrating the genetic and environmental etiology that mimics that of the human. In the Villin-cre, Msh2loxp/loxp, TgfbRIIhu/hu mice (VMshThu), homozygous inactivation of Msh2 in intestinal and colonic epithelial cells causes tissue tissue-specific dMMR. Further, ?G? residues in an otherwise ?A? stretch in the mouse TgfbRll gene were altered by CRISPR/Cas9 to be oligoA, replicating the oligoA in the human gene that makes TgbRll a key target of dMMR. The mice develop intestinal tumors with the unique histopathologies of flat adenoma progressing to mucinous invasive carcinoma characteristic of LS/dMMR tumors, and every tumor has a mutation in the oligo A of the ?humanized? TgfbRII gene. Feeding a purified rodent western-style diet (NWD1) to VMshThu mice shifts tumor penetrance into the colon, producing the same unique pathologies as in human LS/dMMR. The NWD1 recapitulates intake for the mouse of several nutrients at levels of each epidemiologically linked in western-societies to higher incidence of colorectal cancer. This new model has very high relevance to human LS, including historical data linking dietary shift in human LS to colon penetrance, as well as for somatically linked dMMR and sporadic colon tumorigenesis in the general population. Our published and submitted data establish that feeding NWD1 to wild-type mice profoundly alters function of intestinal stem cells in homeostasis and tumorigenesis, with underlying changes in stem cell programming and accumulation, spectra and signature of mutations. Therefore, we hypothesize shift to colon tumor penetrance by feeding NWD1 to VMshThu mice is due to altered colonic stem cell function.
Aim 1 dissects alterations in function, programming, epigenetic and genetic changes induced by NWD1 in VMshThu mice in Lgr5hi, Bmi1+ and Aldh1+ colonic stem cell populations. Emphasis is on the Tgfb, Wnt signaling, DNA repair and oxidative phosphorylation pathways, and extended globally.
Aim 2 addresses the fundamental public health issue of persistence of specific programming, epigenetic and genetic changes in long-lived colonic stem cells and their progeny upon switching the protumorigenic NWD1 back to purified control diet.
Aim 3 dissects molecular changes that characterize the progression of the unique benign flat adenomas to mucinous invasive carcinomas. Further, using unique RNAseq data bases of LS patients compared to average risk individuals for the uninvolved mucosa, and for adenomas and carcinomas of LS and dMMR patients, correspondence between genes and pathways in the mouse model and in human will be determined. This will prioritize targets for development of markers of risk and progression and for further mechanistic dissection.

Public Health Relevance

A new mouse model closely reflects the combination of genetic and dietary factors that cause development of human colon tumors that have defects in DNA mis-match repair. This model will be used to understand the molecular mechanisms of this genetic-environmental interaction in stem cells, how changes in stem cells persist over long periods and if they can be reversed, and which changes are fundamental in the progression from normal primed mucosa to benign and on to invasive tumors. The potential clinical importance in detection, prevention and treatment of these unique tumors is very high.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
6R01CA222358-02
Application #
9854402
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Emenaker, Nancy J
Project Start
2018-07-05
Project End
2023-05-31
Budget Start
2019-01-01
Budget End
2019-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
081266487
City
Bronx
State
NY
Country
United States
Zip Code
10461