FEATURED INVESTIGATOR
KARL MÜNGER, PHD

Dr. Karl Münger’s work is centered on understanding the role of human papillomavirus (HPV) in cervical cancer. Cervical cancer is the second leading cause of cancer death in women worldwide. Of special interest to Dr. Münger are two HPV proteins, E6 and E7, the only two viral proteins that are consistently expressed in cervical cancers.

Background

A native of Switzerland, Dr. Münger received his undergraduate degree and Ph.D. in biochemistry from the University of Zurich. After completing his doctoral degree in 1986, Dr. Münger did a postdoctoral fellowship in molecular virology in Peter Howley’s laboratory at the National Institutes of Health in Bethesda, MD, staying on as Visiting Associate in the Laboratory of Tumor Virus Biology until 1993. In 1993, he accepted a position as Assistant Professor in the Department of Pathology at the Harvard Medical School. In 2006, he joined Dr. Elliott Kieff ’s viral oncology group at the Channing Laboratory, a multidisciplinary research division of the Brigham and Women’s Hospital and Harvard Medical School. He currently is associate professor in the Department of Medicine, Harvard Medical School and Associate Virologist at Brigham and Women’s Hospital.

Research

HPV E6 and E7 are small proteins of approximately 150 and 100 amino acids in length, respectively, that are absolutely needed to induce and maintain the transformed (abnormal) phenotype of cervical epithelial cells. Cervical cancer is a unique model for studying human tumor development because it is the only solid tumor for which the molecular mechanism of the underlying carcinogen (HPV) is well defined. The E6 and E7 proteins function by associating with and subverting the functions of the host cellular tumor suppressor pathways. The best known of the E6 and E7 targets are the p53 and retinoblastoma (pRB) tumor suppressor proteins, respectively. These tumor suppressor pathways, or their downstream effectors, are rendered defective by mutation in the majority of all human solid tumors. Dr. Münger believes that identifying additional cellular targets of the E6 and E7 oncoproteins will lead to the discovery of other tumor suppressor pathways that similarly contribute to carcinogenesis in a wide range of human tumors. Dr. Münger and colleagues are using proteomics to identify and characterize the full set of cellular proteins with which the HPV E7 oncoprotein associates. They have also begun a high throughput screening procedure using small-hairpin RNA (shRNA) to identify novel signal transduction pathways that contribute to cervical carcinogenesis. Using this approach, they intend to identify specific proteins that are absolutely essential to abnormal cells that express HPV oncoproteins.

Laboratory

Dr. Münger prefers his laboratory to be “midsize and manageable.” The precise number fluctuates between 8 and 10 researchers. In addition to a laboratory manager, most of the remaining members are postdoctoral fellows and graduate students. Dr. Münger and his colleagues participate in weekly floor meetings “where scientists, postdoctoral fellows, and graduate students meet to present and discuss the present status of their work. This is exciting since many of the top virology laboratories in the field are concentrated at the Channing Laboratory, and the open lab architecture, in fact, fosters collaboration. The labs are basically intermingled in this large open space, with Elliott Kieff ’s laboratory on one side of the floor, and Ken Kaye’s, Fred Wang’s and my own laboratories on the other side of the floor. For a viral oncologist, it’s an exceptionally exciting place to work.”

funding

The principal source of funding for Dr. Münger’s research is the National Institutes of Health.

Collaborations

Dr. Münger has numerous scientific collaborations locally, nationally, and internationally, including Jim DeCaprio and Marc Vidal at the Dana Farber Cancer Institute, Nick Dyson at Massachusetts General Hospital, Ed Harlow at Harvard Medical School, Phil Hinds at the New England Medical Center, Irene Georgakoudi at Tufts University in Medford, Michael Feld at Massachusetts Institute of Technology, Paul Lambert in Madison, Wisconsin, and Stefan Duensing, who trained in the Münger Laboratory and is now Assistant Professor at the University of Pittsburgh Cancer Center. Dr. Münger is proud to have mentored many basic and physician-scientists who have gone on to establish their own research laboratories across the country.

Importance of Being at the Brigham

The concentration of great physicians at the Brigham is a tremendous value to a basic scientist. “I have always made sure that I had a medical doctor or person with a medical background in my laboratory,” Dr. Münger explains,  because they help us to focus our research on problems of real clinical relevance.”

Future

Science has realized such an incredible revolution of technologies—technologies that were only dreamed of in the early 1990s. As Dr. Münger relates, “early in my career in the 1990’s I feared that I would end my career doing exactly the same work I was doing when I started. The rapid pace of technological evolution has eliminated this fear. We need to embrace and incorporate these technologies into the mainstream of cancer research. The combination of all these methods—proteomics, chemical biology, gene array technology, and SNP analysis—should permit us to readily identify disease genes throughout the entire human genome. One example of this is our recent foray into cancer systems biology. Systems biology tells us that you can’t look at proteins just in isolation. They must be viewed as elements of a system and studied for their interactions with other elements of the system, with the goal of creating a map of cellular interactions. The fundamental hypothesis of our study is that the targets of viral oncoproteins will be important signal integrators. Using viral oncoproteins, we should be able to refine the cellular interaction map and then couple the findings with gene expression and SNP studies as well as biochemical proteomic analyses. Elliott Kieff ’s laboratory, Jim DiCaprio’s laboratory, and my laboratory are collaborating with Marc Vidal at Dana Farber Cancer Institute and collaborators at other local institutions in this effort. Harnessing these technologies by combining all of the proteomic and gene array studies into a single comprehensive picture is a major challenge that will require a huge investment in research power and funding.”

Selected References
  1. Rozenblatt-Rosen O, Deo RC, Padi M, Adelmant G, Calderwood MA, Rolland T, Grace M, Dricot A, Askenazi M, Tavares M, Pevzner S, Abderazzaq F, Byrdsong D, Carvunis A-R, Chen AA, Cheng J, Correll M, Duarte M, Fan C, Feltkamp MC, Ficarro SB, Franchi R, Garg BK, Gulbahce N, Hao T, Holthaus A, James R, Korkhin A, Litovchick L, Mar JC, Pak TR, Rabello S, Rubio R, Shen Y, Singh S, Spangle JM, Tasan M, Wanamaker S, Webber JT, Roecklein-Canfield J, Johannsen E, Barabási A-L, Beroukhim R, Kieff E, Cusick ME, Hill DE, Münger K, Marto JA, Quackenbush J, Roth FP, DeCaprio JA, Vidal M: Interpreting cancer genomes using systematic host perturbations by tumour virus proteins, Nature 2012; 487:491-5. PMCID: PMC3408847
  2. Spangle JM, Münger K. The HPV16 E6 oncoprotein causes prolonged receptor protein tyrosine kinase signaling and enhances internalization of phosphorylated receptor species. PLoS Pathog. 2013 Mar;9(3):e1003237. doi: 10.1371/journal.ppat.1003237. Epub 2013 Mar 14. PubMed PMID: 23516367; PubMed Central PMCID: PMC3597533.
  3. Meyers JM, Spangle JM, Münger K. The human papillomavirus type 8 E6 protein interferes with NOTCH activation during keratinocyte differentiation. J Virol. 2013 Apr;87(8):4762-7. doi: 10.1128/JVI.02527-12. Epub 2013 Jan 30. PubMed PMID:  23365452; PubMed Central PMCID: PMC3624394.
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