Principal Investigator

Leonard H
Awardee Organization

Albert Einstein College Of Medicine
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

A Major Nutritional Effect on Intestinal Stem Cells and Tumors

We have dissected impact of a western style purified diet (NWD1) on intestinal and colonic tumorigenesis. NWD1 recapitulates mouse intake of key nutrients each at their levels epidemiologically linked to higher risk for intestinal cancer in western developed countries. We established that NWD1 amplifies and accelerates intestinal tumors in many mouse genetic models, regardless of genetic etiology and aggressiveness driven by single or multiple genetic drivers. Moreover, when fed to wild-type mice long-term, we and others established that NWD1 causes sporadic intestinal and colon tumors. At least 1 year before these sporadic tumors develop, there is altered maturation of epithelial cells and underlying molecular pathways in the histopathologically normal mucosa. This led to investigating how the cell and molecular biology of intestinal stem cells are altered by the NWD1, We reported the surprising discovery that NWD1 compromises stem cell functions of Lgr5hi cells in intestinal homeostasis and tumorigenesis, but that this is compensated for by mobilization of Bmi1+ cells as stem cells for these functions. Moreover, genetic and dietary experiments identify decreased vitamin D exposure and Vdr signaling as important in these effects, consistent with Clevers' reported stem cell expression signature strongly implicating Vdr signaling in Lgr5hi stem cell functions. Further, we noted that mouse experiments on intestinal stem cells have used diets establishing vitamin D levels well above the range of that for the US population. This raises significant questions regarding which and how stem cells function in homeostasis and tumorigenesis. Extensive new data since the prior review (submitted for publication) establish profound effects of dietary exposures: i) on programming of Lgr5hi and Bmi1+ cells (RNAseq); ii) on capacity for DNA repair in these cells; iii) on subsequent extent, spectrum and signature of mutations that accumulate in cells of these crypt compartments (sequencing of FACS isolated single cells). Aim 1 addresses the hypothesis that dietary induced changes in Lgr5hi stem cell programming, function, and epigenetic alterations can be exceptionally long lived, and therefore that stem cells can be used as “sentinel cells” to monitor the ability of dietary intervention to modulate these alterations as potential markers of risk and targets for intervention. This will provide fundamental data regarding coordination of genes and pathways in regulation of stem cell function, identification of markers of relative risk, and how intervention strategies can be optimized. Aim2 of the initial submission has been largely accomplished, and Aim 2 is revised to investigate the hypothesis that altered DNA repair is important in differential dietary effects on tumorigenesis from the Lgr5+ and Bmi1+ populations when conditional Apc mutations are targeted specifically to each of these cell populations. Aim2 also determines the impact of diet on the nature of mutations in Apc and throughout the genome in the tumors that arise. Aim 3 determines impact of diet on tumor histopathology and programming of tumor epithelial cells when tumors are initiated from either the Lgr5+ or Bmi1+ stem cell compartments. RNAscope and a novel method of transcriptional imaging then determine relative contribution of Lgr5+ and Bmi1+ stem cells to intestinal homeostasis and tumorigenesis under different dietary conditions.


  • Tadesse S, Corner G, Dhima E, Houston M, Guha C, Augenlicht L, Velcich A. MUC2 mucin deficiency alters inflammatory and metabolic pathways in the mouse intestinal mucosa. Oncotarget. 2017 Apr 6;8(42):71456-71470. doi: 10.18632/oncotarget.16886. eCollection 2017 Sep 22. PMID: 29069719
  • Li W, Zimmerman SE, Peregrina K, Houston M, Mayoral J, Zhang J, Maqbool S, Zhang Z, Cai Y, Ye K, Augenlicht LH. The nutritional environment determines which and how intestinal stem cells contribute to homeostasis and tumorigenesis. Carcinogenesis. 2019 Aug 22;40(8):937-946. PMID: 31169292
  • Choi J, Houston M, Wang R, Ye K, Li W, Zhang X, Huffman DM, Augenlicht LH. Intestinal stem cell aging at single-cell resolution: Transcriptional perturbations alter cell developmental trajectory reversed by gerotherapeutics. Aging cell. 2023 May;22(5):e13802. Epub 2023 Mar 2. PMID: 36864750
  • Wolfson SJ, Hitchings R, Peregrina K, Cohen Z, Khan S, Yilmaz T, Malena M, Goluch ED, Augenlicht L, Kelly L. Bacterial hydrogen sulfide drives cryptic redox chemistry in gut microbial communities. Nature metabolism. 2022 Oct;4(10):1260-1270. Epub 2022 Oct 20. PMID: 36266544
  • Li W, Peregrina K, Houston M, Augenlicht LH. Vitamin D and the nutritional environment in functions of intestinal stem cells: Implications for tumorigenesis and prevention. The Journal of steroid biochemistry and molecular biology. 2020 Apr;198:105556. Epub 2019 Nov 26. PMID: 31783155
  • Li W, Houston M, Peregrina K, Ye K, Augenlicht LH. Effects of Diet Choice on Stem Cell Function Necessitate Clarity in Selection and Reporting. Cell stem cell. 2020 Jul 2;27(1):11-12. PMID: 32619509
  • Choi J, Zhang X, Li W, Houston M, Peregrina K, Dubin R, Ye K, Augenlicht L. Dynamic Intestinal Stem Cell Plasticity and Lineage Remodeling by a Nutritional Environment Relevant to Human Risk for Tumorigenesis. Molecular cancer research : MCR. 2023 Aug 1;21(8):808-824. PMID: 37097719
  • Li W, Houston M, Peregrina K, Ye K, Augenlicht LH. Effects of diet choice on stem cell function necessitate clarity in selection and reporting. Cell stem cell. 2021 Apr 1;28(4):779. PMID: 33798423
  • Bedard GT, Gilaj N, Peregrina K, Brew I, Tosti E, Shaffer K, Tyler PC, Edelmann W, Augenlicht LH, Schramm VL. Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition. The Journal of biological chemistry. 2024 Jan;300(1):105492. Epub 2023 Nov 23. PMID: 38000655