Yilmaz Lab

Overview

My laboratory studies how adult stem cells and their microenvironment adapt to various diets in the context of tissue regeneration, aging, and cancer initiation. However, the mechanisms through which diet perturbs stem and progenitor cell biology and leads to diseases, such as cancers, are poorly understood. Towards this end, we are studying how diverse dietary interventions such as calorie restriction (CR), fasting and high fat diet (HFD)-induced obesity impact intestinal stem cell (ISC) and progenitor function in the mammalian intestine.  Since ISCs, like all adult stem cells, possess the ability to self-renew (i.e. generate daughter stem cells) and the capacity for multipotent differentiation (i.e. generate lineage-committed progenitors and ultimately all mature tissue-specific cell types), they likely play an important role in remodeling the intestine in response to diet-induced physiologies. A majority of ISCs express the leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) and reside at the bottom intestinal crypts nestled between Paneth cells in the small intestine and deep secretory cells in the colon; both Paneth cells and deep secretory cells constitute a significant component of the stem cell cellular neighborhood or “niche”.  Such niche cells elaborate myriad growth factors and cues necessary for the maintenance of Lgr5+ ISCs.  This intercalated positioning of Lgr5+ ISCs and their niche cells make the intestine an elegant system for deciphering the autonomous versus non-autonomous (or niche-mediated) effects of different diets and the gut microbiome on stem cell self-renewal and differentiation and how changes in ISCs contribute to cancer formation and growth.

In addition, my lab has developed numerous tools and techniques that enable Crispr/Cas9 genetically defined intestinal cancer organoids that can be endoscopically transplanted into the colons of recipient mice. Furthermore, we have devised endoscopic methods for mucosal directed Crispr/Cas9 genome editing to establish intestinal tumors. The development of such tools will enable us to dissect how tumor initiation, growth, aging, metastasis, immunosurveillance, and drug resistance are influenced by diverse dietary states and the gut microbiome, including the goals of this current application.

Publications

Cheng CW, Biton M, Haber AL, Gunduz N, Eng G, Gaynor L, Tripathi S, Calibasi-Kocal G, Rickelt S, Butty VL, Moreno M, Iqbal AM, Bauer-Rowe KE, Mylonas K, Whary MT, Levine SS, Hynes RO, Mino-Kenudson M,  Deshpande V, Boyer LA, Fox JG, Mihaylova MM, Regev A, and Yilmaz ÖH. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell 2019;178(5):1115-1131

Mihaylova M, Cheng CW, Cao AQ, Tripathi S, Mana MD, Bauer-Rowe KE, Abu-Remailleh M, Clavin L, Erdemir A, Lewis C, Freinkman E, Huang Y, Bell G, Deshpande V, Carmeliet P, Katajisto P, Sabatini DM, Yilmaz ÖH. Fasting-Activated Fatty Acid Oxidation Enhances Intestinal Stem Cell Function. Cell Stem Cell. 2018; 22(5):769-778.

Roper J, Tammela T, Akkad A, Almeqdadi M, Santos, SB, Jacks T, Yilmaz ÖH. Colonoscopy-based colorectal cancer modeling in mice with CRISPR-Cas9 genome editing and organoid transplantation. Nature Protocols. 2018;13(2):217-234.

Roper J, Tammela T, Cetinbas NM, Akkad A, Roghanian A, Rickelt S, Almeqdadi M, Wu K, Oberli M, Sánchez-Rivera FJ, Park Y, Liang X, Eng G, Azimi R, Kedrin D, Neupane R, Beyaz S, Sicinska ET, Bass A, Suarez Y, Yoo J, Chen L, Taylor MS, Zukerberg L, Katajisto P, Tsichlis PN, Lees J, Deshpande V, Chen J, Hynes RO, Langer R, Bhutkar A, Jacks T, Yilmaz ÖH. Epithelial genome editing and organoid transplantation models of
colorectal cancer. Nature Biotechnology. 2017; 35(6):569-576.

Beyaz S, Mana MD, Roper J, Kedrin D, Saadatpour A, Hong SJ, Bauer-Rowe KE, Xifaras ME, Akkad A, Pinello L, Katz Y, Shinagare S, Abu-Remaileh M, Lamming D, Guo G, Selig M, Nielsen GP, Gupta N, Ferrone C, Deshpande V, Yuan GC, Orkin SH, Sabatini DM, Yilmaz ÖH. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature. 2016; 531(7592):53-8.