# Dietary control of stem cells in physiology and cancer

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $409,486

## Abstract

PROJECT SUMMARY
Organismal diet has a profound impact on tissue regeneration, aging, and disease in mammals. However, the
mechanisms through which diet perturbs stem and progenitor cell biology and leads to diseases such as
cancer are poorly understood. With the rise of obesity in the US population—more than 1 in 3 adults are obese
–understanding the relationship between diet, stem cell biology, and cancer incidence takes on great
importance.
 Focused on the mammalian intestine, we find that a pro-obesity high fat diet (HFD) augments the number
and niche-independent function of Lgr5+ stem cells. Mechanistically, our studies indicate that a HFD induces a
robust peroxisome proliferator-activated receptor delta (PPAR-d) signature in intestinal stem cells (ISCs) and
progenitors (non-stem cells), and pharmacologic activation of PPAR-d recapitulates the effects that a HFD has
on these cells. Furthermore, like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid
constituents of the HFD enhances the self-renewal potential of these organoids in a PPAR-d dependent
manner. Interestingly, both HFD- and agonist-activated PPAR-d signaling endow progenitors with the
organoid-initiating capacity normally restricted to stem cells. In fact, agonist-enforced PPAR-d signaling permits
these progenitors to form in vivo tumors upon loss of the tumor suppressor Apc. These observations provide a
possible pathway for diet through modulating PPAR-d activation to alter not only the function of intestinal stem
and progenitor cells but also their capacity to initiate tumors. Many questions remain regarding the impact of a
HFD on the intestine, such as the in vivo, cell type-specific roles of PPAR-d in this process, and the identity of
progenitor subsets that emerge in this diet to drive tumor development. Also, although PPAR-d is a master
transcriptional regulator of genes involved in fatty acid oxidation (FAO), it is unclear whether intestinal stem
and progenitor cells or tumors that arise in a HFD rely on this PPAR-d-activated FAO metabolic program for
their maintenance.
 Specifically, we will test the hypotheses that PPAR-d mediates the in vivo effects of a HFD in ISCs and
progenitors in intestinal homeostasis and tumor initiation (Aim 1); that a subset of non-stem cell progenitors
acquire stemness and tumorigenic potential in a HFD and with enforced PPAR-d signaling (Aim 2); that a HFD
or enforced PPAR-d signaling render ISCs, progenitors, or established tumors metabolically reliant on fatty
acid oxidation for their maintenance (Aim 3).

## Key facts

- **NIH application ID:** 10058815
- **Project number:** 5R01CA211184-05
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Omer Yilmaz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $409,486
- **Award type:** 5
- **Project period:** 2016-12-23 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058815

## Citation

> US National Institutes of Health, RePORTER application 10058815, Dietary control of stem cells in physiology and cancer (5R01CA211184-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10058815. Licensed CC0.

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