Research Institute in Oncology and Hematology

Geoff Hicks

Genetics

Contact:Dr Geoff Hicks PhD

Regenerative Medicine Program
669 Basic Med Sci Bldg
745 Bannatyne Avenue
University of Manitoba
Winnipeg, Mb R3E 0J9

Phone: (204) 318-5287
Lab: (204) 318-5289
Email: Dr Geoff Hicks PhD



Functional Analysis of the Mammalian Genome

Now that the human genome has been decoded, the next major challenge to the Genome Initiative will be to bridge the gap between these rapidly expanding DNA sequence databases and gene function. To utilize the sequence information for large-scale functional studies, we have developed a process called tagged-sequence mutagenesis to disrupt genes expressed in mouse embryo-derived stem (ES) cells and to characterize each mutation by direct DNA sequencing. More recently, we have developed precision gene targeting in ES cells, which allows us to make defined changes in cancer genes. The new technology allows us to knockout cancer genes, or to make the very same mutations we know occur in the human cancers. The ability to induce, characterize and maintain mutations in ES cells circumvents many limitations associated with conventional mammalian genetics, and will greatly increase the number of mutant alleles (typically loss of function mutations) by which gene functions can be studied in mice and in cell lines derived from such mice. The process will facilitate a functional analysis of a mammalian genome in vivo and will provide animal models for human genetic diseases. Currently, we are leading Canada's effort to develop an Embryonic Stem Cell Library with defined knockout gene mutations in each of the 23,000 known genes in the mouse. ES cell clones containing specific mutations in genes of interest will be made available to investigators as a national resource. Functional Analysis of TLS, EWS, and ALR in Normal Development and in Oncogenic

Transformation

Mutations (from the ES cell library) transmitted to the germline will focus on genes known or suspected to be involved in tumour progression. Understanding the normal function of a gene in mammalian development is a powerful approach to understanding how the oncogene contributes to the respective cancer. The focus of the lab is on genes which are translocated in the development of human cancers; specifically, the TLS and EWS genes. While the translocations and the associated cancers for these genes are highly characterized, little is known about function of the genes themselves or how they contribute to tumour development. Our approach is to analyze developmental defects in mice that are either deficient for specific gene (and are otherwise genetically identical to wild-type mice). For example TLS is a gene that is translocated in many human soft tissue sarcomas and myelogenous leukemia. Functional analysis of mice that are homozygous for the TLS/FUS mutation has revealed TLS plays a critical role in the normal development of blood cells and in maintaining genomic stability. Using this approach, we have now discovered the how changes in TLS during cancer specifically prevent its normal role to limit cell proliferation and correct mutations in other genes -- both of which are hallmarks of cancer itself.

Regenerative Medicine and Cancer Stem Cells

Most recently, Dr. Hicks has been appointed Director of the Regenerative Medicine Program in the University of Manitoba's Faculty of Medicine. The 8 Principal Investigators of the program will focus on stem cell-based applications for the treatment of human disease, including cancer, cardiovascular disease, and spinal cord injury repair.

Team Members

  • Molly Pind (Research Associate)
  • Songyan Liu (Director of Bioinformatics)
  • Agnes Fresnoza (Technician)
  • Suhaila Selamat (Technician)
  • Berardino Petrelli (MSc)

    Invited Seminars and Presentations at Symposia and Meetings

    Chair and Meeting Organizer, CIHR New PI Meeting. St Gabriel, Quebec, Oct 30th - Nov 1st, 2015.
    “P53 is an Oncogene! ……..Isn’t it?” RIOH Retreat, Mennonite Heritage Centre, Steinbach, September 24, 2015.
    “Genetic Analysis of FUS mutations in Cancer and ALS: Insights to common links.” Jilin University, September 4, 2015.
    “Genetic Variations Underlying Risk Assessment in Fetal Alcohol Spectrum Disorders.” Songyan Liu and Geoff Hicks. Jilin University, September 4, 2015.
    “Genetic Variation Underlying Risk Assessment in FASD and ALS.” Manitoba Neuroscience Network 6th Annual Meeting, Winnipeg, June 11, 2015
    “Vitamin A Deficiency induced by Prenatal Alcohol Exposure: A Genetic Model of Fetal Alcohol Syndrome” Geoffrey G. Hicks, Berardino Petrelli, Arzu Öztürk, Molly Pind and Abraham Fainsod. Canadian Nutrition Society Annual Conference, Winnipeg, May 28-31, 2015.
    “A FASD Mouse Model: Biochemically Mimicking Alcohol Exposure using Gsc promoter driven Cyp26A1 cDNA.” Berardino Petrelli, Arzu Oztürk, Molly Pind, Abraham Fainsod, Geoffrey G. Hicks. 2015 Canadian Neuroscience Meeting, Vancouver, May 24-27th, 2015.
    Chair and Meeting Organizer, CIHR New PI Meeting. St Gabriel, Quebec, Nov 21-23, 2014. “Dysregulated Alternative Splicing and Autoregulation: A novel mechanism underlying the pathogenesis of Amyotrophic Lateral Sclerosis with FUS mutations.” Yueqin Zhou, Songyan Liu, Arzu Oztürk, Geoffrey G. Hicks. Shanghai Normal University, Shanghai, China, Oct 20, 2014.
    “Role of FUS/TLS in Stem Cell Diseases & Disorders.” Yueqin Zhou, Songyan Liu, Arzu Oztürk, Geoffrey G. Hicks. Jilin University, Chanchung, China, October 17th, 2014.
    “Dysregulated Alternative Splicing and Autoregulation: A Novel Mechanism Underlying the Pathogenesis of Amyotrophic Lateral Sclerosis with FUS Mutations.” Yueqin Zhou, Songyan Liu, Arzu Oztürk, Geoffrey G. Hicks. Jilin University, Chanchung, China, October 17th, 2014.
    “FUS/TLS targets mRNAs and miRNAs involving DNA damage response. Yueqin Zhou, Songyan Liu, Arzu Oztürk, Geoffrey G. Hicks. AACR New Horizons in Cancer Research Conference, Shanghai, October 9-12, 2014.
    “Discovering the Epigenetic Signatures Associated with Fetal Alcohol Spectrum Disorder.” Jim DAVIE, Marc DEL BIGIO, Brenda ELIAS, Abraham FAINSOD, Mojgan RASTEGAR and Geoff HICKS. International Human EpiGenome Consortium Meeting, Vancouver, Oct 6 – 8th, 2014.
    “Genetic Modeling FASD in Mice.” Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism 2014 Joint Congress. MOLECULAR ETIOLOGY OF FASD: NEW INSIGHTS FROM ANIMAL MODELS (Mini-Symposium Co- Organizer and Co-Chair), Bellevue, WA, June 21-25, 2014.
    “Genetics of FASD.” 2nd Canada Israel International Fetal Alcohol Consortium Symposium. (Symposium Co-Organizer and Chair). Jerusalem, Israel, June 5, 2014.
    “ALS-FUS mutants are compromised in alternative splicing and autoregulation.” 10th Annual ALS CANADA Research Forum. Toronto, May 3 – 5, 2014.
    “Familial ALS with FUS mutations.” 2014 Western Medical Diagnostic Laboratories Conference, Winnipeg, May 1st, 2014
    Fetal Alcohol Spectrum Disorder; Alcohol Competes With Vitamin A Metabolism During Early Embryogenesis.” 5th International Conference on FASD, Vancouver, Feb. 2013. “Developing Pre-Clinical Mouse Models for FASD and Human Disease.” 5th International Conference on FASD, Vancouver, Feb. 2013.
    “microRNA and mRNA Expression Profiles Identify Regulatory Networks Coordinated by FUS/TLS.” (Abstract, Zhou Y, Ozturk A, Liu S, Hicks GG). Keystone Symposia: Noncoding RNA in Development and Cancer, Vancouver, Jan 20- 25, 2013
    “Canada-Israel International Fetal Alcohol Consortium.” International FASD Collaborations Symposium (Symposium Organizer and Co-chair), Winnipeg, Feb 2013.
    “Genetically Modeling Rare Human Diseases in Mouse Models.” Hefei University, Hefei, Nov. 2012.
    “Mammalian Functional Genomics Centre and Genetic Modeling Centre – Disease Modeling in Three Stories.” Department of Pharmacology, Norman Bethune Medical School, Jilin University, Changchun, Nov. 2012.
    “Genetically Engineered mouse models for Discovery and Pre-Clinical Validation.” Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, Nov. 2012.
    “Determining the FASD Code: A Genetic and Epigenetic Approach to Evaluate Individual Risk and Treatment for Fetal Alcohol Spectrum Disorder.” MICB Retreat, Winnipeg, Sept 2012.
    “GSC::Cyp26A – a mouse model of FASD.” NeuroDevNet NCE AGM, Toronto, Sept. 2012.
    “Engineering Discovery and Pre-Clinical Models for Childhood Cancers.” Western Canada Children’s Cancer Research Network Symposium, Edmonton, May 2012.
    “Genetically engineering mouse models to assess new prevention strategies for Fetal Alcohol Syndrome.” Limmud Winnipeg 2012, Winnipeg, February 2012
    “Molecular analysis of the ethanol effect in Fetal Alcohol Syndrome suggests a preventive approach.” Genetics and Epigenetics of FASD, St Pierre, Reunion Island, France, March 2012. “New insights into Fetal Alcohol Spectrum Disorder preventive.” Reunion Island Prefecture, St. Denis, France, March 2012.

    Professional Service

    1.Canadian Genetic Disease Network Centre of Excellence Investigator. 2000-2008
    2.NIH Ewing Sarcoma Initiative. 2002-present
    3.International Gene Trap Consortium. 1999-present
    4.International Mouse Mutagenesis Consortium. 2001-present
    5.International Knockout Mouse Project Consortium. 2004-present
    6.Federation of International Mutant Mouse Resources. 2005-present
    7.Canadian Mouse Consortium, founding member. 2004-present
    8.International Knockout Mouse Consortium, founding member. 2004-present

    Professional Activities

    1. Director - Regenerative Medicine Program in the University of Manitoba's Faculty of Medicine.
    2. Director, Mammalian Functional Genomics Centre. 1999-present
    3. Canadian Institutes of Health Research, Reviewer for G, CPT and MCC Panels. 1999-present
    4. Chair, CIHR Institute of Genetics New Principal Investigator Symposium. 2001-present
    5. Scientific Director, Gene Modeling Centre, University of Manitoba. 1999-present
    6. Scientific Advisory Board Member, Genome BC, Pathogenomics of Innate Immunity. 2006- present
    7. CIHR Institute of Genetics Advisory Panel. 2001-present
    8. Scientific Advisory Board Member, Genome Quebec, Gene Regulators in Disease. 2006-present
    9. Scientific Advisory Board Member, BC Transgenics Centre. 2007-present
    10. Scientific Director, Genetic Modeling Centre, University of Manitoba. 2007-present
    11. Manitoba Health Research Council, Research Advisory Committee. 2008-present

    Publications since 2010

    PubMed Listed Publications
    1. de Angelis MH, Nicholson G, Selloum M, White JK, Morgan H, Ramirez-Solis R, Sorg T, Wells S, Fuchs H, Fray M, Adams DJ, Adams NC, Adler T, Aguilar-Pimentel A, Ali-Hadji D, Amann G, André P, Atkins S, Auburtin A, Ayadi A, Becker J, Becker L, Bedu E, Bekeredjian R, Birling MC, Blake A, Bottomley J, Bowl MR, Brault V, Busch DH, Bussell JN, Calzada-Wack J, Cater H, Champy MF, Charles P, Chevalier C, Chiani F, Codner GF, Combe R, Cox R, Dalloneau E, Dierich A, Di Fenza A, Doe B, Duchon A, Eickelberg O, Esapa CT, Fertak LE, Feigel T, Emelyanova I, Estabel J, Favor J, Flenniken A, Gambadoro A, Garrett L, Gates H, Gerdin AK, Gkoutos G, Greenaway S, Glasl L, Goetz P, Da Cruz IG, Götz A, Graw J, Guimond A, Hans W, Hicks GG., Hölter SM, Höfler H, Hancock JM, Hoehndorf R, Hough T, Houghton R, Hurt A, Ivandic B, Jacobs H, Jacquot S, Jones N, Karp NA, Katus HA, Kitchen S, Klein-Rodewald T, Klingenspor M, Klopstock T, Lalanne V, Leblanc S, Lengger C, le Marchand E, Ludwig T, Lux A, McKerlie C, Maier H, Mandel JL, Marschall S, Mark M, Melvin DG, Meziane H, Micklich K, Mittelhauser C, Monassier L, Moulaert D, Muller S, Naton B, Neff F, Nolan PM, Nutter LM, Ollert M, Pavlovic G, Pellegata NS, Peter E, Petit-Demoulière B, Pickard A, Podrini C, Potter P, Pouilly L, Puk O, Richardson D, Rousseau S, Quintanilla-Fend L, Quwailid MM, Racz I, Rathkolb B, Riet F, Rossant J, Roux M, Rozman J, Ryder E, Salisbury J, Santos L, Schäble KH, Schiller E, Schrewe A, Schulz H, Steinkamp R, Simon M, Stewart M, Stöger C, Stöger T, Sun M, Sunter D, Teboul L, Tilly I, Tocchini-Valentini GP, Tost M, Treise I, Vasseur L, Velot E, Vogt-Weisenhorn D, Wagner C, Walling A, Wattenhofer-Donze M, Weber B, Wendling O, Westerberg H, Willershäuser M, Wolf E, Wolter A, Wood J, Wurst W, Yildirim AÖ, Zeh R, Zimmer A, Zimprich A; EUMODIC Consortium, Holmes C, Steel KP, Herault Y, Gailus-Durner V, Mallon AM, Brown SD. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics. Nat Genet. 2015 Sep;47(9):969-78. doi: 10.1038/ng.3360. Epub 2015 Jul 27.
    2. Kino Y, Washizu C, Kurosawa M, Yamada M, Miyazaki H, Akagi T, Hashikawa T, Doi H, Takumi T, Hicks GG., Hattori N, Shimogori T, Nukina N. FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2015 Apr 25;3:24. doi: 10.1186/s40478-015-0202-6.
    3. Zhou Y, Liu S, Oztürk A, Hicks GG.. FUS-regulated RNA metabolism and DNA damage repair: Implications for amyotrophic lateral sclerosis and frontotemporal dementia pathogenesis. Rare Dis. 2014 Jun 12;2:e29515. doi: 10.4161/rdis.29515. eCollection 2014.
    4. Zhou Y, Liu S, Liu G, Oztürk A, Hicks GG.ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation.PLoS Genet. 2013 Oct;9(10):e1003895. doi: 10.1371/journal.pgen.1003895. Epub 2013 Oct 31.
    5. Lagier-Tourenne C, Polymenidou M, Hutt KR, Vu AQ, Baughn M, Huelga SC, Clutario KM, Ling SC, Liang TY, Mazur C, Wancewicz E, Kim AS, Watt A, Freier S, Hicks GG, Donohue JP, Shiue L, Bennett CF, Ravits J, Cleveland DW, Yeo GW. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci. 2012 Nov;15(11):1488-97. doi: 10.1038/nn.3230. Epub 2012 Sep 30.
    6. Beaulieu CL, Samuels ME, Ekins S, McMaster CR, Edwards AM, Krainer AR, Hicks GG, Frey BJ, Boycott KM, Mackenzie AE. A generalizable pre-clinical research approach for orphan disease therapy. Orphanet J Rare Dis. 2012 Jun 15;7(1):39.
    7. Lin CP, Choi YJ, Hicks GG, He L.The emerging functions of the p53-miRNA network in stem cell biology. Cell Cycle. 2012 Jun 1;11(11):2063-72. Epub 2012 Jun 1.
    8. Choi YJ, Lin CP, Ho JJ, He X, Okada N, Bu P, Zhong Y, Kim SY, Bennett MJ, Chen C, Ozturk A, Hicks GG, Hannon GJ, He L. miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol. 2011 Oct 23;13(11):1353-60. doi: 10.1038/ncb2366.
    9. Ringwald M, Iyer V, Mason JC, Stone KR, Tadepally HD, Kadin JA, Bult CJ, Eppig JT, Oakley DJ, Briois S, Stupka E, Maselli V, Smedley D, Liu S, Hansen J, Baldock R, Hicks GG, Skarnes WC. (2011). The IKMC web portal: a central point of entry to data and resources from the International Knockout Mouse Consortium. Nucleic Acids Res. 39:D849-55.
    10. Choi, Y., Lin, Y-P., Xiong, Y., Kim, S., Bu, P., Bennett, M., He, Y., Hannon, G., Chen, C., Ozturk, A., Hicks, GG. and He, L. (2010). miR-34a miRNA provides a barrier for somatic cell reprogramming. Nature Cell Biology, in press.
    11. Sabbir, MG., Wigle, N., Loewen, S., Gu, Y., Buse,C., Hicks, GG. and Mowat, MRA (2010). Identification and characterization of Dlc1 isoforms in the mouse and study of the biological function of a single gene trapped isoform. BMC Biology, 8:17-26.
    12. Xu, K.. Nieuwenhuis, E., Cohen, B., Wang, W., Canty, A., Danska, J., Coultas, L., Rossant, J., Wu, M., Piscione, T., Gossler, A., Hicks, GG., Hui, C.-c., Henkelman, RM., Yu, L., Sled, L., Gridley, T. and Egan, S. (2010). Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis. Am J Physiol Lung Cell Mol Physiol. 298:45-56.


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