The nutritional environment determines which and how intestinal stem cells contribute to homeostasis and tumorigenesis

Author:

Li Wenge1,Zimmerman Samuel E2,Peregrina Karina1,Houston Michele1,Mayoral Joshua3,Zhang Jinghang4,Maqbool Shahina5,Zhang Zhengdong5,Cai Ying5,Ye Kenny6,Augenlicht Leonard H17

Affiliation:

1. Department of Medicine, Albert Einstein College of Medicine, Ullmann, Bronx, NY, USA

2. Systems and Computational Biology, Albert Einstein College of Medicine, Ullmann, Bronx, NY, USA

3. Pathology, Albert Einstein College of Medicine, Ullmann, Bronx, NY, USA

4. Microbiology and Immunology, Albert Einstein College of Medicine, Ullmann, Bronx, NY, USA

5. Genetics, Albert Einstein College of Medicine, Ullmann, Bronx, NY, USA

6. Epidemiology and Population Health, Albert Einstein College of Medicine, Ullmann, Bronx, NY, USA

7. Cell Biology, Albert Einstein College of Medicine, Ullmann, Bronx, NY, USA

Abstract

Abstract Sporadic colon cancer accounts for approximately 80% of colorectal cancer (CRC) with high incidence in Western societies strongly linked to long-term dietary patterns. A unique mouse model for sporadic CRC results from feeding a purified rodent Western-style diet (NWD1) recapitulating intake for the mouse of common nutrient risk factors each at its level consumed in higher risk Western populations. This causes sporadic large and small intestinal tumors in wild-type mice at an incidence and frequency similar to that in humans. NWD1 perturbs intestinal cell maturation and Wnt signaling throughout villi and colonic crypts and decreases mouse Lgr5hi intestinal stem cell contribution to homeostasis and tumor development. Here we establish that NWD1 transcriptionally reprograms Lgr5hi cells, and that nutrients are interactive in reprogramming. Furthermore, the DNA mismatch repair pathway is elevated in Lgr5hi cells by lower vitamin D3 and/or calcium in NWD1, paralleled by reduced accumulation of relevant somatic mutations detected by single-cell exome sequencing. In compensation, NWD1 also reprograms Bmi1+ cells to function and persist as stem-like cells in mucosal homeostasis and tumor development. The data establish the key role of the nutrient environment in defining the contribution of two different stem cell populations to both mucosal homeostasis and tumorigenesis. This raises important questions regarding impact of variable human diets on which and how stem cell populations function in the human mucosa and give rise to tumors. Moreover, major differences reported in turnover of human and mouse crypt base stem cells may be linked to their very different nutrient exposures.

Funder

National Cancer Institute

National Institutes of Health

American Institute for Cancer Research

New York State Stem Cell Science

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,General Medicine

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