Ömer H. Yilmaz, MD, PhD

"The adult intestine is maintained by stem cells that require a cellular neighborhood, or niche, consisting in part of Paneth cells. By better understanding how intestinal stem cells and their Paneth cell niche adapt to diverse diets, we hope to identify and develop new strategies that prevent and reduce the growth of cancers involving the intestinal tract."

Ömer Yilmaz is the Eisen and Chang Career Development Associate Professor of Biology at the Koch Institute for Integrative Cancer Research at MIT and a gastrointestinal pathologist at the Massachusetts General Hospital and Harvard Medical School. He is a graduate of the University of Michigan Medical School, where he performed his thesis work under the guidance of Professor Sean Morrison. He has also spent three years as a Postdoctoral Fellow in the laboratory of Professor David M. Sabatini, a member of the Whitehead and Koch Institutes. In 2014 he established his lab, which focuses on understanding how intestinal stem cells and their microenvironment adapt to diverse diets in the context of tissue regeneration, aging, and cancer initiation/progression. His achievements, to date, have been recognized with a Harold Weintraub Award (2007), a V Scholar Award (2015), a Pew-Stewart Trust Fellowship (2016), a Sidney Kimmel Fellowship (2016), a Sabri Ulker International Science Prize (2018), and AAAS Martin and Rose Wachtel Cancer Research Prize (2018).

Research Summary

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.

For more information about Professor Yilmaz’s research, please visit the Yilmaz lab webpage.

Selected 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 (In press)

Pentinmikko N, Iqbal S, Mana M, Andersson S, Cognetta AB 3rd, Suciu RM, Roper J, Luopajärvi K, Markelin E, Gopalakrishnan S, Smolander OP, Naranjo S, Saarinen T, Juuti A, Pietiläinen K, Auvinen P, Ristimäki A, Gupta N, Tammela T, Jacks T, Sabatini DM, Cravatt BF, Yilmaz ÖH, Katajisto P. Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium. Nature. 2019 Jul; 571(7765):398-402.

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, and Yilmaz ÖH. Fasting-Activated Fatty Acid Oxidation Enhances Intestinal Stem Cell Function. Cell Stem Cell 2018. May 3:22(5):769-778

Yilmaz, ÖH. Dietary regulation of the origins of cancer. Science Translational Medicine 2018. Aug 8;19(453).

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 Feb;13(2):217-234.

Roper J, Tammela T, Cetinbas NM, Akkad A, Roghanian A, Rickelt S, Almeqdadi M, Wu K, Oberli MA, Sánchez-Rivera F, ... Yilmaz ÖH. In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis. Nat Biotechnol. 2017; 35: 569–576.

Haber AL, Biton M, Rogel N, Herbst RH, Shekhar K, Smillie C, Burgin G, Delorey TM, Howitt MR, Katz Y, Tirosh I, Beyaz S, Dionne D, Zhang M, Raychowdhury R, Garrett WS, Rozenblatt-Rosen O, Shi HN, Yilmaz O, Xavier RJ, Regev A. A single-cell survey of the small intestinal epithelium. Nature. 2017 Nov 16;551(7680):333-339.

Beyaz S, Mana MD, Roper J, Kedrin D, Saadatpour A, Hong SJ, Bauer-Rowe KE, Xifaras ME, Akkad A, Arias E, Pinello L, Katz Y, Shinagare S, Abu-Remaileh M, Mihaylova MM, Lamming DW, Dogum R, Guo G, Bell GW, Selig M, Nielsen GP, Gupta N, Ferrone CR, Deshpande V, Yuan GC, Orkin SH, Sabatini DM, Yilmaz ÖH.  High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature. 2016; 531: 53–58.

Yilmaz ÖH, Katajisto P, Lamming DW, Gültekin Y, Bauer-Rowe KE, Sengupta S, Birsoy K, Dursun A, Yilmaz VO, Selig M, Nielsen GP, Mino-Kenudson M, Zukerberg LR, Bhan AK, Deshpande V, Sabatini DM. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature. 2012; 486: 490–495.

Yilmaz ÖH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, Morrison SJ. 2006. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441: 475–482.

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