Professor Ohh received his PhD from the University of British Columbia and was a MRC/NCIC postdoctoral fellow in the HHMI laboratory of Nobel laureate William G. Kaelin Jr. at the Dana-Farber Cancer Institute and Harvard Medical School.
Professor Ohh contributed to the pioneering work that defined the fundamental oxygen-sensing mechanism that governs metazoan cellular adaptation to changes in oxygen levels, and the paradigm-shifting research that revealed an additional layer of regulation of the canonical RAS GTPase cycle.
He is a recipient of the Canadian Cancer Society’s Bernard and Francine Dorval Prize, Premier’s Research Excellence Award and Canada Research Chair in Molecular Oncology.
Role of tumour suppressors and oncoproteins in cancer biology
Cancer is a genetic disease caused by alterations in tumour suppressor genes and oncogenes.
Our research mission is to elucidate the molecular mechanisms governing the function of two major cancer-associated proteins called von Hippel-Lindau (VHL) tumour suppressor protein and RAS oncoprotein with the supposition that lessons learned would provide fundamental understanding of cell biology and lay the basic foundation for the development of rational anti-cancer therapeutics.
1. VHL in solid tumours
Oxygen is essential for eukaryotic life and inextricably linked to the evolution of multicellular organisms.
Proper cellular response to changes in oxygen tension during normal development or pathological processes, such as heart disease and cancer, is ultimately regulated by the transcription factor called hypoxia-inducible factor (HIF).
Tumour cells are inevitably challenged with limited oxygen availability as the growth of the tumour mass surpasses the diffusional capacity of oxygen from the nearest blood vessel. To overcome this crisis, tumour cells initiate the hypoxic response to trigger various adaptive responses, including anaerobic metabolism, angiogenesis and increased production of oxygen-carrying red blood cells.
This is accomplished by the stabilization of HIF transcription factor, which escapes oxygen-dependent destructive targeting by VHL tumour suppressor-containing E3 ubiquitin ligase complex under hypoxia.
Clinically relevant is the observation that mutation or loss of VHL causes VHL disease, which is characterized by the development of tumours in multiple organs such as the brain, spinal cord, retina, inner ear, pancreas, adrenal gland, and kidney.
Furthermore, the extent of HIF expression correlates with disease aggressiveness and patient prognosis across a wide range of tumours from breast, prostate, and colon to kidney cancer; underscoring the importance of oxygen-sensing VHL-HIF pathway in oncogenesis.
2. RAS in human cancer
Mutations in RAS and various other components of the RAS signaling pathways are among the most common genetic alterations in human cancers and have also been identified in several developmental syndromes such as Noonan syndrome, Costello syndrome and cardiofaciocutaneous syndrome.
The three human RAS oncogenes (H‐RAS, N‐RAS, and K‐RAS) encode highly related 188-189 amino acid proteins.
They are canonical members of a large superfamily consisting of more than 150 cellular members of small monomeric GTPase proteins, which function as ‘molecular switches’ in a number of signaling pathways that regulate vital cellular functions.
Like other GTP-binding proteins, RAS cycles between the inactive GDP and the active GTP bound forms through conformational changes near the nucleotide-binding site localized to the switch I and switch II regions.
Over the past few decades, it has become clear that the activity or the oncogenic potential of RAS is dependent on the non-receptor tyrosine kinase Src to regulate essential cellular pathways for proliferation, differentiation and survival of eukaryotic cells. However, the precise molecular interplay between RAS and Src remains an outstanding mystery.
Understanding the molecular mechanisms governing RAS will provide invaluable insights into the fundamental processes in cell biology and the pathogenesis of many forms of human cancer as well as numerous developmental syndromes.
Research training and opportunities
Our research approach is multidisciplinary with focus on molecular biology and protein biochemistry. The research environment is highly interactive with state-of-the-art equipment and facilities and is an excellent training ground for outstanding graduate students and postdoctoral fellows who wish to pursue a career in academia.
Past members have garnered competitive national scholarships and been recruited to prestigious institutions such as:
- Memorial Sloan Kettering Cancer Center
- Dana-Farber Cancer Institute
- MD Anderson Cancer Center
- Stanford, Yale, M.I.T., Harvard
Training opportunities are currently available for prospective graduate students pursuing PhD or MD/PhD and for postdoctoral fellows. Candidates are encouraged to directly contact Professor Ohh.
Hypoxia-inducible factor underlies von Hippel-Lindau disease stigmata. Ohh M, Taber CC, Ferens FG, Tarade D. Elife. 2022 Aug 30;11:e80774
The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors. Gebregiworgis T, Kano Y, St-Germain J, Radulovich N, Udaskin ML, Mentes A, Huang R, Poon BPK, He W, Valencia-Sama I, Robinson CM, Huestis M, Miao J, Yeh JJ, Zhang ZY, Irwin MS, Lee JE, Tsao MS, Raught B, Marshall CB, Ohh M, Ikura M. Nature Communications. 2021 Nov 1;12(1):6274.
Nucleolar RNA polymerase II drives ribosome biogenesis. Abraham KJ, Khosraviani N, Chan JNY, Gorthi A, Samman A, Zhao DY, Wang M, Bokros M, Vidya E, Ostrowski LA, Oshidari R, Pietrobon V, Patel PS, Algouneh A, Singhania R, Liu Y, Yerlici VT, De Carvalho DD, Ohh M, Dickson BC, Hakem R, Greenblatt JF, Lee S, Bishop AJR, Mekhail K. Nature. 2020 Jul 15. doi: 10.1038/s41586-020-2497-0.
Evolution of metazoan oxygen-sensing involved a conserved divergence of VHL affinity for HIF1α and HIF2α. Tarade D, Lee JE, Ohh M. Nature Communications. 2019 Jul 23;10(1):3293.
Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation. Kano Y, Gebregiworgis T, Marshall CB, Radulovich N, Poon BPK, St-Germain J, Cook JD, Valencia-Sama I, Grant BMM, Herrera SG, Miao J, Raught B, Irwin MS, Lee JE, Yeh JJ, Zhang ZY, Tsao MS, Ikura M, Ohh M. Nature Communications. 2019 Jan 15;10(1):224.
Translational and HIF1α-dependent metabolic reprogramming underpin metabolic plasticity and responses to kinase inhibitors and biguanides. Hulea L, Gravel SP, Morita M, Cargnello M, Uchenunu O, Im YK, Lehuédé C, Ma EH, Leibovitch M, McLaughlan S, Blouin MJ, Parisotto M, Papavasiliou V, Lavoie C, Larsson O, Ohh M, Ferreira T, Greenwood C, Bridon G, Avizonis D, Ferbeyre G, Siegel P, Jones RG, Muller W, Ursini-Siegel J, St-Pierre J, Pollak M, Topisirovic I. Cell Metabolism. 2018 Dec 4;28(6):817-32.
HIF2α-pVHL complex reveals broad genotype-phenotype correlations in HIF2α-driven disease. Tarade D, Robinson CM, Lee JE, Ohh M. Nature Communications. 2018 Aug 22;9(1):3359.
Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis. Bunda S, Burrell K, Heir P, Zeng L, Alamsahebpour A, Kano Y, Raught B, Zhang ZY, Zadeh G, Ohh M. Nature Communications. 2015 Nov 30;6:8859.
Src promotes GTPase activity of Ras via tyrosine 32 phosphorylation. Bunda S, Heir P, Srikumar T, Cook JD, Burrell K, Kano Y, Lee JE, Zadeh G, Raught B, Ohh M. Proc Natl Acad Sci USA. 2014 Sep 9;111(36):E3785-94.
Hypoxia promotes ligand-independent EGFR signaling via HIF-mediated upregulation of caveolin-1. Wang Y, Roche O, Xu C, Moriyama EH, Heir P, Chung J, Roos FC, Chen Y, Finak G, Milosevic M, Wilson BC, Teh BT, Park M, Irwin MS, Ohh M. Proc Natl Acad Sci USA. 2012 Mar 27;109(13):4892-7.
Tumor strengths and frailties: Cancer SUMmOns Otto’s metabolism. Ohh M. Nature Medicine. 2012 Jan 6;18(1):30-1.
Loss of JAK2 regulation via VHL-SOCS1 E3 ubiquitin heterocomplex underlies Chuvash polycythemia. Russell RC, Sufan RI, Zhou B, Roche O, Sybingco SS, Bunda S, Heathcote SA, Richmond TD, Heir P, Chow VWK, Hickey MM, Fuller FH, Barber DL, Cheresh DA, Simon MC, Kim WY, Irwin MS, Ohh M. Nature Medicine. 2011 Jun 19;17(7):845-53.
NEDD8 pathways in cancer, sine quibus non. Watson IR, Irwin MS, Ohh M. Cancer Cell. 2011 Feb 15;19(2):168-76.
Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Niemeyer CM, Kang M, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Stary J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML. Nature Genetics. 2010 Sep;42(9):794-800.
Regulation of endocytosis via the oxygen-sensing pathway. Wang Y, Roche O, Yan M, Finak G, Evans AJ, Metcalf JL, Hast BE, Hanna SC, Wondergem B, Furge KA, Irwin MS, Kim WY, Teh BT, Grinstein S, Park M, Marsden PA, Ohh M. Nature Medicine. 2009 Mar;15(3):319-24.
pVHL’s kryptonite: E2-EPF UCP. Ohh M. Cancer Cell. 2006 Aug;10(2): 95-7.
HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Kirscher MW, Asara JM, Lane WS, Kaelin WG Jr. Science. 2001 Apr 20;292(5516):464-8.
Ubiquitination of HIF requires direct binding to the beta-domain of the von Hippel-Lindau protein. Ohh M, Park CW, Ivan M, Hoffman MA, Kim T-Y, Huang LE, Pavletich N, Chau V, Kaelin WG Jr. Nature Cell Biology. 2000 Jul;2(7):423-7.
The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov A, Louis DN, Gavin BJ, Kley N, Iliopoulos O, Kaelin WG Jr. Molecular Cell. 1998 Jun;1(7): 959-68.
Honours and Awards
Canadian Cancer Society's Bernard and Francine Dorval Prize
Premier’s Research Excellence Award
Canada Research Chair in Molecular Oncology