Faculty: Lara Collier
|Dept:||Assisstant Professor, Pharmacy|
|Contact:|| 4117 Rennebohm |
|Training Areas:||Molecular & Cellular Pharmacology|
Research in the Collier laboratory focuses on using forward genetic approaches to understanding the molecular basis of cancer initiation, progression and therapy resistance. We use the Sleeping Beauty (SB) transposon system as an insertional mutagen for cancer gene discovery in mouse models of human cancer. We have generated mice that suffer transposon mutagenesis in essentially all cells of the body. Most of these mice develop leukemia due to insertional mutagenesis of cancer genes in the hematopoietic system, but gliomas also occur at low penetrance. In addition to frank tumors, we have also observed hyperproliferative lesions in the prostate glands of these mice. We have used these tumors to identify new candidate cancer genes. In leukemia, we have identified a poorly studied kinase as a candidate tumor suppressor gene. We hypothesize that it functions during mitosis to prevent improper segregation of chromosomes to daughter cells, and are therefore investigating if it modulates the response of leukemia cells to chemotherapeutic agents that act as mitotic poisons. We have also identified a signaling molecule as a candidate glioma oncogene. We are pursuing genetic studies in mice to determine if this gene is necessary or sufficient for glioma formation in vivo. We hypothesize that these studies will determine if inhibitors that target this signaling pathway should be investigated as therapies for human glioma. We are working to generate a glioma specific SB model for use in future genetic and pre-clinical studies. The SB system is also being used to study the genetic basis of therapy resistance in both gliomas and prostate cancer using cell culture and animal models. In addition to using the SB system for cancer gene identification, the laboratory is also studying a novel mouse model for leukemia that we discovered and named Spontaneous dominant leukemia (Sdl). We are using the Sdl model to study the molecular events driving tumor initiation and progression and are taking a positional cloning approach to identify the affected gene. We hypothesize that the mutant gene in Sdl mice will also function as a tumor suppressor gene or oncogene in human leukemia. Future avenues of study in the laboratory also include continued analysis of SB-induced tumors, research on the function of additional candidate cancer genes we identify using SB and determining if these genes have a role in tumor formation in humans.
Honors & Awards
- 2008: Robinson Travel Award (to attend “The Society for Neuro-Oncology annual scientific meeting”)
- 2006 - present: K01 Howard Temin award from the NCI
- Bagley BN, Keane TM, Maklakova VI, Marshall JG, Lester RA, Cancel MM, Paulsen AR, Bendzick LE, Been RA, Kogan SC, Cormier RT, Kendziorski C, Adams DJ, Collier LS. A dominantly acting murine allele of Mcm4 causes chromosomal abnormalities and promotes tumorigenesis. PLoS Genet. 2012;8(11):e1003034. doi: 10.1371/journal.pgen.1003034. Epub 2012 Nov 1. PMID: 23133403
- Pérez-Mancera PA, Rust AG, van der Weyden L, Kristiansen G, Li A, Sarver AL, Silverstein KA, Grützmann R, Aust D, Rümmele P, Knösel T, Herd C, Stemple DL, Kettleborough R, Brosnan JA, Li A, Morgan R, Knight S, Yu J, Stegeman S, Collier LS, ten Hoeve JJ, de Ridder J, Klein AP, Goggins M, Hruban RH, Chang DK, Biankin AV, Grimmond SM; Australian Pancreatic Cancer Genome Initiative, Wessels LF, Wood SA, Iacobuzio-Donahue CA, Pilarsky C, Largaespada DA, Adams DJ, Tuveson DA. The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. Nature. 2012 Apr 29;486(7402):266-70. doi: 10.1038/nature11114. Erratum in: Nature. 2013 Feb 21;494(7437):390. Scarlett, Christopher J [added]; Kaplan, Warren [added]; Scarpa, Aldo [added], Das, Amithabad [corrected to Das, Amitabha]. PMID: 22699621
- Bergerson RJ, Collier LS, Sarver AL, Been RA, Lugthart S, Diers MD, Zuber J, Rappaport AR, Nixon MJ, Silverstein KA, Fan D, Lamblin AF, Wolff L, Kersey JH, Delwel R, Lowe SW, O'Sullivan MG, Kogan SC, Adams DJ, Largaespada DA. An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model. Blood. 2012 May 10;119(19):4512-23. doi: 10.1182/blood-2010-04-281428. Epub 2012 Mar 16. PMID: 22427200
- Wu X, Northcott PA, Dubuc A, Dupuy AJ, Shih DJ, Witt H, Croul S, Bouffet E, Fults DW, Eberhart CG, Garzia L, Van Meter T, Zagzag D, Jabado N, Schwartzentruber J, Majewski J, Scheetz TE, Pfister SM, Korshunov A, Li XN, Scherer SW, Cho YJ, Akagi K, MacDonald TJ, Koster J, McCabe MG, Sarver AL, Collins VP, Weiss WA, Largaespada DA, Collier LS, Taylor MD. Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 2012 Feb 15;482(7386):529-33. doi: 10.1038/nature 10825. PMID 22343890
- Bender AM, Collier LS, Rodriguez FJ, Tieu C, Larson JD, Halder C, Mahlum E, Kollmeyer TM, Akagi K, Sarkar G, Largaespada DA, Jenkins RB (2010). Sleeping beauty-mediated somatic mutagenesis implicates CSF1 in the formation of high-grade astrocytomas. Cancer Res. 70(9):3557-65. PMID: 20388773
- Keng VW, Villanueva A, Chiang DY, Dupuy AJ, Ryan BJ, Matise I, Silverstein KAT, Sarver S, Starr TK, Akagi K, Tessarollo L, Collier LS, Powers S, Lowe SW, Jenkins NA, Copeland NG, Llovet JM, and Largaespada DA. (2009). A conditional transposon-based insertional mutagenesis screen for hepatocellular carcinoma-associated genes in mice. In press at Nature Biotechnology.
- Thielen JL, Volzing KG, Collier LS, Green LE, Largaespada DA, and Marker PC. (2007). Markers of prostate region-specific epithelial identity define anatomical locations in the mouse prostate that are molecularly similar to human prostate cancers. Differentiation. 75:49-61.
- Geurts AM, Collier LS, Geurts JL, Oseth LL, Bell ML, Mu D, Lucito R, Godbout SA, Green LE, Lowe SW, Hirsch BA, Leinwand LA, and Largaespada DA. (2006). Gene mutations and genomic rearrangements in the mouse as a result of transposon mobilization from chromosomal concatemers. PloS Genetics. 29:2
- Geurts AM, Hackett CS, Bell JB, Bergemann TL, Collier LS, Carlson CM, Largaespada DA, and Hackett PB. (2006). Structure-based prediction of insertion-site preferences of transposons into chromosomes. Nucleic Acids Res. 34:2803-11.
Invited Review Articles and Book Chapters
- Largaespada DA and Collier LS. (2008). Identification of transposon-genomic DNA junctions. Methods Mol Biol. 435:95-108.
- Collier LS and Largaespada DA. (2007). Transposable elements and the dynamic somatic genome. Genome Biology. 8:S5.
- Collier LS and Largaesapda DA. (2007). Transposons for somatic mutagenesis: Sleeping Beauty and beyond. Genome Biology. 8:S15.
- Collier LS and Largaespada DA. (2006). Transforming science: cancer gene identification. Curr Opin Genet Dev. 16:23-9.
- Collier LS and Largaespada DA. (2005). Hopping around the tumor genome: transposons for cancer gene discovery.Cancer Res. 65:9607-10.
Invited Talks and Seminars /Abstract Platform Presentations:
- “Institute for Molecular Biology, University of Oregon Seminar Series” Eugene, Oregon. October 2008.
- “Genetics Colloquium, University of Wisconsin, Madison”. Madison, WI. September 2008.
- “Hospital for Sick Children Seminar Series” Toronto, Canada May 2007.
- “Keystone Meeting: Mouse Models at the Frontiers of Cancer Discovery” Whistler, Canada March 2007.
- “BWH Mouse Mutagenesis Workshop”, Boston, MA December 2006.
- “Integrative Molecular Analysis Technologies (IMAT) 7th Annual Principal Investigators Meeting”, Bethesda, MD, September 2006.
- “4th Annual International Meeting on Transposon Research”, Minneapolis, MN, June 2006.
- Biology Department Seminar Series, Grinnell College, Grinnell, IA, May 2006.
- Genetics, Cell Biology, and Development Inaugural Department Retreat, Afton, MN, October 2005.
- Live interview discussing cancer genetics, WCCO Radio, Minneapolis, MN, July 2005.
- “3rd Annual International Meeting on Transposon Research”, Minneapolis, MN, June 2005.
- “Society for Neuro-Oncology's 13th Annual Scientific Meeting”, Las Vegas, NV, November 2008.
- “Mechanisms and Models in Cancer”, Cold Spring Harbor Laboratory, NY, August 2008.
- “Conference of Transposition and Animal Biotechnology”, Minneapolis, MN, June 2007.
- “AACR Special Conference, Innovations in Prostate Cancer Research” December 2006, San Francisco, CA.
- “Society for Basic Urologic Research 16th Annual Meeting” November 2006, Phoenix, AZ.
- “AACR Special Conference, Mouse Models of Cancer” October 2006, Cambridge, MA.
- “15th Annual University of Minnesota Symposium in Developmental Biology” September 2006, Minneapolis, MN.
- “American Association for Cancer Research 97th Annual Meeting” April 2006, Washington, DC.
- “Society for Basic Urologic Research 15th Annual Meeting” December 2005, Miami, FL.
- “70th Symposium: Molecular Approaches to Controlling Cancer”, June 2005, Cold Spring Harbor, NY.
- “Cancer and Development” Keystone Meeting, February 2005, Banff, CA.
- “2nd Annual International Meeting on Transposon Research”, June 2004, Minneapolis, MN.
- “Frontiers in Genome Engineering: Building a Better Mouse” conference on mouse genetics, June 2004, Nashville, TN.
- “1st Annual International Meeting on Transposon Research”, July 2003, Minneapolis, MN.
- “43rd Annual Drosophila Research Conference”, Genetics Society of America, April 2002, San Diego, CA.
- “Society for Developmental Biology Annual Meeting”, July 1997, Stanford, CA.
- Member, The Society for Neuro-Oncology.
- Attended “ENDO08” meeting, June 2008, San Francisco, CA.
- Attended “American Association for Cancer Research, 93rd Annual Meeting”, April 2002, San Francisco, CA.
- Attended “Pathobiology of Cancer Workshop”, American Association for Cancer Research, July 2001, Keystone, CO.
- Attended “42nd Annual Drosophila Research Conference”, Genetics Society of America, March 2001, Washington, DC.
- Student Member to Graduate Admission Committee, January 2001, Program in Cancer Biology, Stanford University.