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).
In the mammalian intestine, Lgr5+ stem cells (ISCs) drive the rapid renewal of the intestinal epithelium and remodel intestinal composition by adjusting their production of daughter stem cells and (non-ISC) progenitors in response to diet-induced cues. In addition to their important role in intestinal homeostasis, these Lgr5+ ISCs also serve as the cell-of-origin for most precancerous adenomatous lesions. Although significant epidemiologic and rodent studies link pro-obesity diets to colon cancer incidence, little is known about how the adaptation of ISCs and progenitors to such diets alters the potential of these cells to form tumors. In this proposal, we will interrogate how a pro-obesity high fat diet impacts intestinal stem and progenitor cell function and the cellular origins of intestinal dysplasia.
|Barriga, Francisco M; Montagni, Elisa; Mana, Miyeko et al. (2017) Mex3a Marks a Slowly Dividing Subpopulation of Lgr5+ Intestinal Stem Cells. Cell Stem Cell 20:801-816.e7|
|Cheng, Chia-Wei; Yilmaz, Ömer H (2017) Starving leukemia to induce differentiation. Nat Med 23:14-15|
|Roper, Jatin; Yilmaz, Ömer H (2017) Metabolic Teamwork in the Stem Cell Niche. Cell Metab 25:993-994|
|Mana, Miyeko D; Kuo, Elaine Yih-Shuen; Yilmaz, Ömer H (2017) Dietary Regulation of Adult Stem Cells. Curr Stem Cell Rep 3:1-8|
|Roper, Jatin; Tammela, Tuomas; Cetinbas, Naniye Malli et al. (2017) In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis. Nat Biotechnol 35:569-576|
|Beyaz, Semir; Yilmaz, Ömer H (2016) Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-? Pathway. Clin Cancer Res 22:5636-5641|