Rama Khokha

Dr Khokha received her M.Sc. from the University of Delhi India in 1978, and her Ph.D. in biochemistry in 1985 from University of Western Ontario.

She was a postdoc at Cancer Research Labs in London, Ontario until 1989 and a von Humboldt Fellow at European Molecular Biology Labs from 1990 to 1992. She began her independent program in 1990 at the London Regional Cancer Centre and then joined Ontario Cancer Institute, Princess Margaret Cancer Centre in Toronto.

She is currently a Professor and Acting Chair for the Department of Medical Biophysics, with a joint appointment at the Department of Laboratory Medicine and Pathobiology, University of Toronto.

Dr. Khokha received Canadian Institutes of Cancer Research Studentship among other awards and was a Canadian Institutes of Cancer Research Scholar. Recently, her work was recognized by the prestigious 2014 Robert L Noble Prize from the Canadian Cancer Society Research Institute.

Research Synopsis

The Khokha lab studies tumour microenvironment and adult stem cell niches.

A major interest is to understand the molecular basis of breast cancer.  To this end, our lab is elucidating the determinants of adult mammary stem cell pools and their regulation by ovarian hormones, with an emphasis on the deciphering the role of progesterone.

Our program is active in developing genetically engineered mouse models for human cancers, and novel tools for cancer gene discovery.

Recent Publications

Jackson HW, Waterhouse P, Sinha A, Kislinger T, Berman HK, Khokha R. Spontaneous stem cell accumulation prevents mammary aging in compound  Timp 1/Timp 3 null mice. Nature Cell Biology. 2015 Mar;17(3):217-27. IF 20.06 – CCSRI/CIHR

Shiah Y-J, Tharmapalan, P, Casey A, Joshi PA, McKee TD, Jackson HW, Beristain AG, Chang-Seng-Yue MA, Bader GD, Lydon J, Waterhouse PD, Boutros PC, Khokha R.  A progesterone-CXCR4 axis controls mammary progenitor cell fate in the adult gland. Stem Cell Reports. 2015 Feb 18. pii: S2213-6711(15)00032-6. – CCSRI/CBCF

Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C, Lee KC, Yung KY, Brenner D, Knobbe-Thomson CB, Cox MA, Elia A, Berger T, Cescon DW, Adeoye A, Brüstle A, Molyneux SD, Mason JM, Li WY, Yamamoto K, Wakeham A, Berman HK, Khokha R, Done SJ, Kavanagh TJ, Lam CW, Mak TW. Gluthione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression. Cancer Cell. 2015 Feb 9;27(2):211-22. IF 27.24 - CIHR

Beristain AG, Molyneux SD, Pujana MA, Joshi PA, Pomroy NC, Di Grappa MA, Chang MC, Krischner LS, Prive G, Khokha R.  PKA signaling directs c-Src activation to generate breast cancers. Oncogene Mar 2014. IF  7.4  - CBCF

Defamie V, Sanchez O, Murthy A, Khokha R. TIMP3 controls cell fate to confer hepatocellular carcinoma resistance. Oncogene. Oct 27, 2014. IF 8.6

Molyneux SD, Waterhouse P, Harris I, Watling CM, Lupien M, Berman H, Sandve GK, Adissu HA, Wood GA, Wunder JS, Mak TW, Khokha R.¬¬ Human somatic cell mutagenesis creates genetically tractable sarcomas. Nature Genetics, 46(9): 964-72, 2014 IF 29.6 Featured in News & Views – GL-2

Alexander CM, Joshi PA, Khokha R, Fully Interlocking: A Story of Teamwork among Breast Epithelial Cells. Dev Cell 28(2): 114-5, 2014. IF 25.3 – IF 13.0 CBCRA/CCSRI

Shimoda M, Luga V, Jackson H, Molyneux SD, Principe S, Fang I, Narala SR, Karamboulas C, Kislinger T, Ailles L, Wrana J, Khokha R. The Timp gene family presents a barrier to the acquisition of the CAF-like cell state. Nature Cell Biology, 16 (9):889-901 2014. IF 20.06 – CIHR

Voura EB, English JL, Yu HYE, Ho AT, Subarsky P, Hill RP, Hojila CV, Khokha R. Proteolysis during tumor cell extravasation in vitro: metalloproteinase involvement across tumor cell types. PLoS One 4.2, 2013. IF 4.41- CIHR

Penfornis P, Cai DZ, Harris MR, Walker R, Licini D, Fernandes JD, Orr G, Koganti T, Hicks C, Induru S, Meyer MS, Khokha R, Barr J, Pochampally RR. High CD49f expression is associated with osteosarcoma tumor progression: a study using patient-derived primary cell cultures. Cancer Med, 3(4):796-811,2014

Wei LZ, Xu Y, Nelles EM, Furlonger C, Wang JC, Di Grappa MA, Khokha R, Medin JA, Paige CJ. Localized interleukin-12 delivery for immunotherapy of solid tumours. J Cell Mol Med. 17 (11): 1465-74, 2013. IF 4.7- CIHR

Khokha R, Murthy A, Weiss A. Metalloproteinases and their natural inhibitors in inflammation and immunity. Nature Reviews Immunology. 13(9): 649 - 65, 2013. IF 33.1

Gorrini C, Baniasadi PS, Harris IS, Silvester J, Inoue S, Snow B, Joshi PA, Wakeham A, Molyneux SD, Martin B, Bouwman P, Cescon DW, Elia AJ, Winterton-Perks Z, Cruickshank J, Brenner D, Tseng A, Musgrave M, Berman HK, Khokha R, Jonkers J, Mak TW, Gauthier ML; BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J Exp Med. 210 (8): 1529 - 44, 2013. IF 13.9 - CBCRA/CBCF

Lee HJ, Gallego-Ortega D, Ledger A, Schramek D, Joshi P, Szwarc MM, Cho C, Lydon JP, Khokha R, Penninger JM, Ormandy CJ. Progesterone drives mammary secretory differentiation via RankL-mediated induction of Elf5 in luminal progenitor cells. Development. 140 (7): 1397- 401, 2013. IF 6.2 - CBCRA/CBCF

Shimoda M, Khokha R. Proteolytic factors in exosomes. Proteomics. 13 (11): 1624 - 36, 2013. IF 4.1

Hewing NJ, Weskamp G, Vermaat J, Farage E, Glomski K, Swendeman S, Chan RV, Chiang MF, Khokha R, Anand-Apte B, Blobel CP.  Intravitreal injection of TIMP3 or the EGFR inhibitor erlotinib offers protection from oxygen-induced retinopathy in mice. Invest Ophthalmol Vis Sci. 54 (1): 864 - 70, 2013. IF 3.4

Fiorentino L, Cavalera M, Menini S, Marchetti V, Mavilio M, Fabrizi M, Conserva F, Casagrande V, Menghini R, Pontrelli P, Arisi I, D'Onofrio M, Lauro D, Khokha R, Accili D, Pugliese G, Gesualdo L, Lauro R, Federici M. Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. EMBO Mol Med. 5 (3): 441 - 55. 2013. IF 10.3

Joshi PA, Di Grappa MA, Khokha R. Active allies: hormones, stem cells and the niche in adult mammopoiesis. Trends Endocrinol Metab 23: 299-309, 2012. IF 8.5 - CBCRA/CBCF

Joshi PA, Khokha R. The mammary stem cell conundrum: is it unipotent or multipotent? Breast Cancer Res 14:305, 2012. IF 5.8 - CBCRA/CBCF

Beristain AG, Narala SR, Di Grappa MA, Khokha R.  Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells. J Cell Sci 125: 943-55, 2012. IF 6.1 – GL-2/NCIC

Murthy A, Shao YW, Defamie V, Wedeles C, Smookler D, Khokha R. Stromal TIMP3 regulates liver lymphocyte populations and provides protection against Th1 T cell-driven autoimmune hepatitis. J Immunol 188(6): 2876-83, 2012. IF.5.8 – CIHR

Murthy A, Shao YW, Narala SR, Molyneux SD, Blobel CP, Zúñiga-Pflücker JC, Khokha R. ADAM17 activation of epidermal Notch regulates atopic barrier immunity and myeloproliferation by suppressing c-Fos-driven transcription of epithelial cytokines. Immunity. 36(1): 105-19, 2012.  IF 24.2 - CIHR. Highlighted in Nat Rev Immunol

McIlwain DR, Lang PA, Maretzky T, Hamada K, Ohishi K, Maney SK, Berger T, Murthy A, Duncan G, Xu HC, Lang KS, Häussinger D, Wakeham A, Itie-Youten A, Khokha R, Ohashi PS, Blobel CP, Mak TW. iROM22 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS. Science. 335(6065): 229-32, 2012 IF 31.4- CIHR

Le Gall SM, Maretzky T, Issuree PD, Niu XD, Reiss K, Saftig P, Khokha R, Lundell D, Blobel CP. ADAM17 is regulated by a rapid and reversible mechanism that controls access to its catalytic site.  J Cell Sci, 123: 3913-22, 2010. IF 6.1- CIHR

Hojilla CV, Jackson HW, Khokha R. TIMP3 regulation of mammary gland involution: timelines of epithelial apoptosis and immune cell influx. PLoS One 2011. IF 4.4 – CBCF/CBCRA

Ebrahem Q, Qi JH, Sugimoto M, Ali M, Sears JE, Cutler A, Khokha R, Vasanji A, Anand-Apte B. Increased neovascularization in mice lacking tissue inhibitor of metalloproteinases-3. Invest Ophthalmol Vis Sci. 52: 6117-23, 2011. - H&S Fdn

Joshi PA, Jackson HW, Beristain AG, Di Grappa MA, Mote P, Clarke C, Stingl J, Waterhouse PD, Khokha R. Progesterone induces adult mammary stem cell expansion.  Nature 465(7299): 803-7, 2010. IF 34.5 – CBCRA Featured in News & Views, National and International press, and highlighted in Nat Rev Cancer.

Molyneux SD, Di Grappa MA, Beristain AG, McKee TD, Wai DH, Paderova, J, Kashyap M, Hu P, Maiuri T, Narala SR, Stambolic V, Squire J, Penninger J, Sanchez O, Triche TJ, Wood GA, Kirschner LS, Khokha R. Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice. J Clin Invest 120(9): 3310-25, 2010. IF 15.4- NCIC

Murthy A, Defamie V, Smookler DS, Di Grappa MA, Horiuchi K, Federici M, Sibilia M, Blobel CP, Khokha R.  Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice. J Clin Invest 120(8): 2731-44, 2010. IF 15.5 CIHR Received an Editorial highlight in Hepatology

Schramek D, Leibbrandt A, Sigl V, Kenner L, Hanada R, Joshi P, Pospisilik JA, Lee H, Aliprantis A, Kiechl S, Willeit J, Ormandy C, Glimcher L, Pasparakis M, Khokha R, Widschwendter M, Achett G, Penninger JM. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer.  Nature, 468(7320): 98-102, 2010. IF 34.5 – CBCRA Received commentary and highlights in Nat Rev Cancer and Nat Rev Endocrinology

Nakajima H, Ito M, Smookler DS, Shibata F, Fukuchi Y, Morikawa Y, Ikeda Y, Arai F, Suda T, Khokha R, Kitamura T. TIMP-3 recruits quiescent hematopoietic stem cells into active cell cycle and expands multipotent progenitor pool. Blood 116(22): 4474-82, 2010. IF 10.6 - CIHR

Koskivirta I, Kassiri Z, Rahkonen O, Oudit GY, Oksjoki S, Liu P; Vuorio E, Khokha R. Mice with Timp4 deletion succumb to induced myocardil infarction but not to cardiac pressure overload. J Biol Chem 285(32): 24487-93, 2010. IF 6.7 - H&S Fdn.

Gill SE, Huizar I, Bench EM, Sussman SW, Wang Y, Khokha R, Parks WC. Tissue inhibitor of metalloproteinases 3 regulates resolution of inflammation following acute lung injury. Am J Pathol 176(1): 64-73, 2010.  IF 5.9 – CIHR

Fiorentino L, Vivanti A, Cavalera M, Marzano V, Fabrizi M, Menini S, Pugliese G, Menghini R, Khokha R, Lauro R, Urbani A, Federici M. Increased TACE activity induces insulin resistance and hepatosteatosis in mice.  Hepatology 51(1): 103-10, 2010. IF 9.8 - CIHR

Reviews and book chapters

Tharmapalan, Pirashaanthy; Khokha R, Adult mammary stem cells: Identity, location and functional assays; Book Title Adult, Stem Cells, 2nd Edition 2013 , Editor: Turksen, Kursad.

Shao Yang, Khokha R, Hill D. Tumor Progression and Metastasis in The Basic Science of Oncology, 5th Edition. Editors, R Bristow, L Harrington, RP Hill & Ian Tannock.

Murthy A, Cruz-Munoz W, Khokha R. 2008. TIMPs: Extracellular modifiers in cancer development.  In The Cancer Degradome—Proteases and Cancer Biology. DR Edwards, G Hoyer-Hansen, F Blasi, BF. Sloane, editors: Springer New York.  373-400. CIHR

Khokha R, Werb Z. Mammary gland reprogramming: Metalloproteinases couple form with function. Cold Spring Harbor Laboratory Press. CSH Perspectives in Mammary Gland Biology. Eds M Bissell, K Polyak, J Rosen. April 3 (4). pii: a004333. doi: 10.1101/cshperspect.a004333, 2011 CBCRA/CBCF

Manuscripts submitted and in preparation

Joshi PA, Waterhouse P, Narala SA, Di Grappa MA, Dougall WC, Penninger JM, Khokha R. Progesterone-driven RANK amplifies Wnt-activated progenitors. – In revision for Stem Cell Reports, CBCRA/CBCF

Chen Y, Molyneux S, Di Grappa M, Waterhouse P, McKee T,  Khokha R. RANKL blockade prevents and treats aggressive osteosarcomas in mice. – In revision for Science Translational Medicine, CBCRA/CBCF

Jackson HW, Khokha R. Invited Review. Tissue inhibitors of metalloproteinases in cancer. Nature Reviews Cancer Outline approved by the Editor. 

Honours and Awards

Name: 2014 Robert L Noble Prize from the Canadian Cancer Society Research Institute.
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