Graduate, post-doctoral, and undergraduate trainees have the opportunity to work with and learn from biochemists, molecular and cell biologists, and bioinformatic and proteomic experts to develop a highly rounded research program in cancer pathology.
The general theme of our research program is to understand the functional mechanisms of somatically mutated or differentially expressed proteins in cancer pathology. The research integrates proteomic, genomic, chemical biology and bioinformatic technologies with more traditional biochemical and molecular biology methodologies. Our goal is to develop large scale integrative programs to understand the causes, and identify therapeutic targets, for multi-factorial diseases such as cancer. To learn more about Dr. Morin's research, read The Protein Link to Cancer, published in the BC Cancer Foundation Spring 2015 Partners in Discovery magazine.
The functions of most proteins are defined by or mediated through interactions with other proteins. These interactions are organized into complex networks regulated, in part, through modulation of protein phosphorylation by an elaborate interconnected system of kinases and phosphatases. We use quantitative proteomic techniques to study how protein networks, protein-protein interactions and post-translational modifications are aberrantly regulated in cancer
Aberrant RNA Processing in Cancer. A major research focus is the regulatory mechanisms of aberrant RNA processing in cancer, particularly the regulation of alternative pre-mRNA splicing and miRNA biogenesis. One program studies the properties of Cyclin Dependent Kinase 12 (CDK12) in breast and ovarian cancers. CDK12 interacts with spliceosomal proteins and RNA Pol2 to coordinately regulate splicing, alternative splicing and transcription elongation. Using global quantitative mass spectrometry methods in CRISPR/Cas9 engineered isogenic cancer cell line models we identify the roles and mechanisms of CDK12 in regulating gene transcription and spliceosome splice site choice. Using small molecule inhibitors of CDK12 kinase activity we probe the biological functions of CDK12 and its cellular targets. A second program studies the oncogenic mechanisms of somatic mutations in the miRNA processing enzyme DICER1 in a broad spectrum of rare developmental cancers. The mutations affect only the RNase IIIb subdomain of DICER1 to abolish expression of 5P miRNAs. We are developing isogenic cell lines and engineered mouse models to study mutant Dicer function.
Mutant Protein Function. An important driver mechanism of oncogenesis is focal or hotspot somatic mutations of protein coding genes. These mutations must impart oncogenic properties to these proteins. In a third program we study the C134W hotspot mutation of FOXL2 in the development of adult granulosa cell tumours (aGCT). We have engineered isogenic cell line models for mutant FOXL2 expression which we are analyzing by integrative proteome profiling, RNA-seq and ChIP-seq. From these experiments we are investigating how this specific mutation changes the protein-protein interactions and transcriptional regulatory properties of FOXL2 to drive tumourigenesis.
Proteomic and Genomic Collaborative Projects. (Proteomics Services) Through the operation of the GSC/BCCA Proteomics Platform, the Morin lab collaborates with more than 40 BCCA, local and non-local cancer researchers to study the mechanistic and functional roles of proteins implicated in a wide variety of cancers. These projects use global and targeted proteomic techniques integrated with genomic methods, such as RNA-seq and ChIP-seq in cancer cell lines, isogenic cell line models, and murine model systems to study aberrant protein function in multiple cancer types. We have developed an ultrasensitive proteome profiling method for the analysis of formalin fixed clinical tumour samples. With this protocol we seek to identify histotype specific biological processes and proteins to find candidate biomarkers and therapeutically targetable proteins and pathways.
"The oncogenic roles of DICER1 RNase IIIb domain mutations in ovarian Sertoli-Leydig cell tumors." Wang Y, Chen J, Yang W, Mo F, Senz J, Yap D, Anglesio MS, Gilks B, Morin GB, Huntsman DG. Neoplasia. 2015 Aug;17(8):650-60.
"MEF2B mutations in non-Hodgkin lymphoma dysregulate cell migration by decreasing MEF2B target gene activation." Pon JR, Wong J, Saberi S, Alder O, Moksa M, Grace Cheng SW, Morin GB, Hoodless PA, Hirst M, Marra MA. Nat Commun. 2015 Aug 6;6:7953.
"Cancer-associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse-strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage." Anglesio MS, Wang Y, Yang W, Senz J, Wan A, Heravi-Moussavi A, Salamanca C, Maines-Bandiera S, Huntsman DG, Morin GB. J Pathol. 2013 Feb;229(3):400-9.
"Interaction of cyclin-dependent kinase 12/CrkRS with cyclin K1 is required for the phosphorylation of the C-terminal domain of RNA polymerase II." Cheng SW, Kuzyk MA, Moradian A, Ichu TA, Chang VC, Tien JF, Vollett SE, Griffith M, Marra MA, Morin GB. Mol Cell Biol. 2012 Nov;32(22):4691-704.
"Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers." Heravi-Moussavi A, Anglesio MS, Cheng SW, Senz J, Yang W, Prentice L, Fejes AP, Chow C, Tone A, Kalloger SE, Hamel N, Roth A, Ha G, Wan AN, Maines-Bandiera S, Salamanca C, Pasini B, Clarke BA, Lee AF, Lee CH, Zhao C, Young RH, Aparicio SA, Sorensen PH, Woo MM, Boyd N, Jones SJ, Hirst M, Marra MA, Gilks B, Shah SP, Foulkes WD, Morin GB, Huntsman DG. N Engl J Med. 2012 Jan 19;366(3):234-42.
"Cytosolic protein interactions of the schizophrenia susceptibility gene dysbindin." Mead C-LR, Kuzyk MA, Moradian A, Wilson GM, Holt RA, Morin GB. J. Neurochemistry. 2010 Jun;113(6):1491-503.
"Large-scale mapping of human protein-protein interactions by mass spectrometry." Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D. Mol Syst Biol. 2007;3:89.
"Expression of Mouse Telomerase Reverse Transcriptase during Development, Differentiation, and Proliferation." Greenberg RA, Allsopp RC, Chin L, Morin GB, DePinho RA. Oncogene. 1998 Apr 2;16(13):1723-30.
"Extension of life-span by introduction of telomerase into normal human cells." Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay, SW, Lichtsteiner L,Wright WE. Science. 1998 Jan 16;279(5349):349-52.
"Reconstitution of Human Telomerase with the Template RNA Component hTR and the Catalytic Protein Subunit hTRT." Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer V M, Holt SE, Bodnar AG, Lichtsteiner S, Kim NW, Trager JB, Taylor RD, Carlos R, Andrews WH, Wright WE, Shay JW, Harley CB, Morin GB. Nature Genetics. 1997 Dec;17(4):498-502.
"Telomerase Catalytic Subunit Homologs from Fission Yeast and Human." Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB, Cech TR. Science. 1997 Aug 15;277(5328):955-9.
"Recognition of a Chromosome Truncation Site Associated with α-Thalassaemia by Human Telomerase." Morin GB. Nature. 1991 Oct 3;353(6343):454-6.
"The Human Telomere Terminal Transferase is a Ribonucleoprotein that Synthesizes TTAGGG Repeats." Morin, GB. Cell. 1989 Nov 3;59(3):521-9.
Gregg Morin's Complete Publications List including selected links to full text articles.