Karen <span>M.</span> Mann, PhD
Researcher

Karen M. Mann, PhD

Academic Rank: Assistant Member

Overview

Discipline

    • Gastrointestinal Oncology
    • Molecular Oncology
    • Malignant Hematology
    • Cancer Biology and Evolution Program

Education & Training

    • Case Western Reserve University, PhD - Genetics
    • National Cancer Institute, Fellow
    • Institute of Molecular and Cell Biology, Fellow
Research

Insertional mutagenesis is a powerful gene discovery tool for cancer biology. Many solid tumor types, including pancreatic cancer, are highly molecularly heterogeneous, which poses a major challenge for identifying genetic events that actively contribute to tumor progression. We combined the Sleeping Beauty (SB) insertional mutagenesis system with a mouse model of pancreatic cancer and identified a number of recurrently mutated genes that cooperate with oncogenic Kras to drive pancreatic cancer progression and metastasis. My lab is focused on characterizing two progression drivers involved in gene transcription and alternative splicing, respectively, and the contribution of their deregulated gene networks to metastasis. We recently reported a new sequencing technology to uncover cooperating SB insertion events in tumors using single cell sequencing. Applying this approach to an SB model of myeloid leukemia, we showed that recurrently activated Ets- related transcription factors Erg and Ets1 operate in different cell populations within the same tumor. Furthermore, these genes have different co-occurring oncogenic partners that may contribute to clonal selection and tumor progression. My lab is using this sequencing approach to characterize the intra- and inter-tumor heterogeneity in our myeloid leukemia model in order to identify clonally selected cooperating oncogenes that contribute to tumorigenesis and can be targeted by single agent or combination therapies. We will use the SB transposon to track genomic changes induced by therapeutic regimens used to treat myeloid leukemia in order to characterize how these agents reprogram gene networks to affect tumor growth.

Publications

  • Newberg JY, Mann KM, Mann MB, Jenkins NA, Copeland NG. SBCDDB: Sleeping Beauty Cancer Driver Database for gene discovery in mouse models of human cancers. Nucleic Acids Res. 2017 Oct. Pubmedid: 29059366.
  • Mann KM, Newberg JY, Black MA, Jones DJ, Amaya-Manzanares F, Guzman-Rojas L, Kodama T, Ward JM, Rust AG, van der Weyden L, Yew CC, Waters JL, Leung ML, Rogers K, Rogers SM, McNoe LA, Selvanesan L, Navin N, Jenkins NA, Copeland NG, Mann MB. Analyzing tumor heterogeneity and driver genes in single myeloid leukemia cells with SBCapSeq. Nat Biotechnol. 2016 Sep;34(9):962-972. Pubmedid: 27479497.
  • Mann KM, Ying H, Juan J, Jenkins NA, Copeland NG. KRAS-related proteins in pancreatic cancer. Pharmacol Ther. 2016 Dec;168:29-42. Pubmedid: 27595930.
  • Goh AM, Xue Y, Leushacke M, Li L, Wong JS, Chiam PC, Rahmat SA, Mann MB, Mann KM, Barker N, Lozano G, Terzian T, Lane DP. Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice. Oncotarget. 2015 Jul;6(20):17968-17980. Pubmedid: 26255629. Pmcid: PMC4627229.
  • Mann KM, Jenkins NA, Copeland NG, Mann MB. Transposon insertional mutagenesis models of cancer. Cold Spring Harb Protoc. 2014 Mar;2014(3):235-247. Pubmedid: 24591685.
  • Mann MB, Jenkins NA, Copeland NG, Mann KM. Sleeping Beauty mutagenesis: exploiting forward genetic screens for cancer gene discovery. Curr Opin Genet Dev. 2014 Feb;24:16-22. Pubmedid: 24657532.
  • Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012 Nov;491(7424):399-405. Pubmedid: 23103869. Pmcid ...
  • Goh AM, Lim CY, Chiam PC, Li L, Mann MB, Mann KM, Menendez S, Lane DP. Using targeted transgenic reporter mice to study promoter-specific p53 transcriptional activity. Proc Natl Acad Sci U S A. 2012 Jan;109(5):1685-1690. Pubmedid: 22307631. Pmcid: PMC3277193.
  • Mann KM, Ward JM, Yew CC, Kovochich A, Dawson DW, Black MA, Brett BT, Sheetz TE, Dupuy AJ, Chang DK, Biankin AV, Waddell N, Kassahn KS, Grimmond SM, Rust AG, Adams DJ, Jenkins NA, Copeland NG. Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc Natl Acad Sci U S A. 2012 Apr;109(16):5934-5941. Pubmedid: 22421440. Pmcid: PMC3341075.
  • Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE. ApoE promotes the proteolytic degradation of Abeta. Neuron. 2008 Jun;58(5):681-693. Pubmedid: 18549781. Pmcid: PMC2493297.
  • Mann KM, Thorngate FE, Katoh-Fukui Y, Hamanaka H, Williams DL, Fujita S, Lamb BT. Independent effects of APOE on cholesterol metabolism and brain Abeta levels in an Alzheimer disease mouse model. Hum Mol Genet. 2004 Sep;13(17):1959-1968. Pubmedid: 15229191.
  • Lehman EJ, Kulnane LS, Gao Y, Petriello MC, Pimpis KM, Younkin L, Dolios G, Wang R, Younkin SG, Lamb BT. Genetic background regulates beta-amyloid precursor protein processing and beta-amyloid deposition in the mouse. Hum Mol Genet. 2003 Nov;12(22):2949-2956. Pubmedid: 14506131.