PhD, University of Western Ontario
At A Glance
- Our focus is on:
- Adult stem cells
- Stem cell niches
- Proteases and tumor microenvironment
- Innovative cancer models and OMICs applications
- Molecular cancer prevention
- World renowned in mammary stem cells and breast cancer
- History of developing superior models for human cancers
- Cancer genomics and translational focus in bone cancer
- Wide scope of biological systems and cutting-edge technologies
- Exceptional track record of publications and successful alumni
Rama Khokha is a Senior Scientist at the Princess Margaret Cancer Centre (PM), University Health Network. She is Professor in the Department of Medical Biophysics, cross appointed to the Department of Laboratory Medicine and Pathobiology, University of Toronto. Dr. Khokha received her MSc from the University of Delhi, India, and PhD in biochemistry in 1985 from University of Western Ontario. She was a postdoctorate fellow 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 1996. 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.
Adult Stem Cell Niches & Tumor Microenvironment
We are working to unravel the biological complexity of tissue homeostasis since its disintegration underlies cancer and disease. Control over structural scaffolds, stem & progenitor cell populations, and instructive signals is essential for healthy aging of tissues. We excel at developing cutting-edge systems including genetically engineered mouse models and primary human cell mutagenesis platforms. We are known for our discoveries in proteolytic regulation of cell signalling, adult stem cell dynamics, and new cancer driver genes that govern tumorigenesis. We are translating our findings to benefit cancer therapy, prevention and cure.
Adult stem cells and Tissue homeostasis
We aim to understand how extrinsic factors regulate stem cell populations in adult tissues. We discovered that progesterone induces adult mammary stem cell expansion via intricate paracrine signalling across distinct epithelial cell populations (Nature 2010; Stem Cell Reports 2015; JAMA Oncology 2015). Sex hormone-driven mechanisms, and their control over breast biology, are our current focus towards developing new means for breast cancer screening, prevention and therapy. Stem cell fate also depends on cellular interactions with its niche. We study how natural protease inhibitors function to construct adequate structural and soluble constituents critical for sustaining and expanding stem cell pools (Nature Cell Biology 2015).
Secreted and cell surface proteases are invariably altered in all human cancers where they impact structural matrix integrity and inflammation. We have developed genetic mouse models and cell systems to globally perturb metalloproteinase networks. This allows us to study their function in cancer initiation and progression, as well as dissect underlying molecular mechanisms. We have shown that proteolysis provides an innate control over powerful signal transduction pathways including TNF, EGFR and Notch signalling during inflammation, tissue regeneration and tumor-stromal interactions (Nature Reviews Immunology 2013; Nature Cell Biology 2014; Immunity 2012; J Clinical Investigation 2010). We are investigating these processes in breast as well as liver and pancreatic cancers (Oncogene 2015).
Cancer Gene Discovery
To complement the global efforts towards cancer gene discovery, we have developed new approaches using Sleeping Beauty transposon mutagenesis for primary human cells in forward genetic screens. Beginning with specific human cells, such as bone-derived cells, we generate de novo, tractable human cancers in mice and then use genomic methods to identify candidate genes that can drive specific cancers or tumor subtypes (Nature Genetics 2014). We have also developed cross-species genomics to leverage other organisms to broaden our reach for discovering new cancer driver genes. Here, we are especially committed to osteosarcoma, a bone cancer that afflicts younger populations and compromises their quality of life (Science Translational Medicine 2015; J Clinical Investigation 2010).
For more detailed information visit the Khokha lab homepage.
- RANKL blockade prevents and treats aggressive osteosarcomas. Chen Y, Di Grappa MA, Molyneux SD, McKee TD, Waterhouse P, Penninger JM, Khokha R. Science Translational Medicine. 2015, 7(317):317ra197. PMID: 26659571
- RANK Signaling Amplifies WNT-Responsive Mammary Progenitors through R-SPONDIN1. Joshi PA, Waterhouse PD, Kannan N, Narala S, Fang H, Di Grappa MA, Jackson HW, Penninger JM, Eaves C, Khokha R. Stem Cell Reports. 2015, 5(1):31-44. PMID: 26095608
- Progesterone Exposure and Breast Cancer Risk: Understanding the Biological Roots.Joshi PA, Goodwin PJ, Khokha R. JAMA Oncol. 2015, 1(3):283-5. PMID: 26181171
- Expansion of stem cells counteracts age-related mammary regression in compound Timp1/Timp3 null mice. Jackson HW, Waterhouse P, Sinha A, Kislinger T, Berman HK, Khokha R. Nature Cell Biology. 2015, 17(3):217-27. PMID: 25706237
- TIMP3 controls cell fate to confer hepatocellular carcinoma resistance. Defamie V, Sanchez O, Murthy A, Khokha R. Oncogene. 2015, 34(31):4098-108. PMID: 25347747
- Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Shimoda M, Principe S, Jackson HW, Luga V, Fang H, Molyneux SD, Shao YW, Aiken A, Waterhouse PD, Karamboulas C, Hess FM, Ohtsuka T, Okada Y, Ailles L, Ludwig A, Wrana JL, Kislinger T, Khokha R. Nature Cell Biology. 2014, 16(9):889-901. PMID: 25150980
- Human somatic cell mutagenesis creates genetically tractable sarcomas. Molyneux SD, Waterhouse PD, Shelton D, Shao YW, Watling CM, Tang QL, Harris IS, Dickson BC, Tharmapalan P, Sandve GK, Zhang X, Bailey SD, Berman H, Wunder JS, Izsvák Z, Lupien M, Mak TW, Khokha R. Nature Genetics. 2014, 46(9):964-72. PMID: 25129143
- Metalloproteinases and their natural inhibitors in inflammation and immunity. Khokha R, Murthy A, Weiss A. Nature Reviews Immunology. 2013, 13(9):649-65. PMID: 23969736
- Notch activation by the metalloproteinase ADAM17 regulates myeloproliferation and atopic barrier immunity by suppressing epithelial cytokine synthesis. Murthy A, Shao YW, Narala SR, Molyneux SD, Zúñiga-Pflücker JC, Khokha R. Immunity. 2012, 36(1):105-19. PMID: 22284418
- Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice. Murthy A, Defamie V, Smookler DS, Di Grappa MA, Horiuchi K, Federici M, Sibilia M, Blobel CP, Khokha R. Journal of Clinical Investigation. 2010, 120(8):2731-44. PMID: 20628198
- Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice. 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. Journal of Clinical Investigation. 2010, 120(9):3310-25. PMID: 20697156
- Progesterone induces adult mammary stem cell expansion. Joshi PA, Jackson HW, Beristain AG, Di Grappa MA, Mote PA, Clarke CL, Stingl J, Waterhouse PD, Khokha R. Nature. 2010 465(7299):803-7. PMID: 20445538