David E. Misek, Ph.D.
Research Associate Professor
It has been well established that there is altered protein expression in human neoplasia. These alterations may manifest themselves as increased (or decreased) levels of specific cellular proteins; as changes in the post-translational modifications of specific proteins, and in the functionality of proteins in critically important cell signaling pathways. These cancer-specific proteomic changes may contribute to tumorigenesis, and may have utility as biomarkers for the early detection of cancer. Our laboratory is focused on the identification and characterization of the altered protein expression and altered protein post-translational modifications in a variety of human cancers, most notably breast cancer and pancreatic cancer. We have two major projects in our laboratory, both of which are funded by either DoD or NIH grant support.
- Characterization of major breast cancer subtypes. Breast cancer is the second leading cause of cancer-related deaths among women in the U.S. Epidemiological data suggest that breast cancer will affect one out of eight American women. Major advances in breast cancer control depend upon improved early detection modalities. Existing biomarkers for breast cancer are inadequate for early diagnosis. Our laboratory is exploring differential protein expression in four major subtypes of breast cancer. We are focused on the identification of key signaling proteins/pathways in the tumor cells, as well as on altered post-translational modifications on secreted/released proteins that may have utility as early detection biomarkers. Through the use of a variety of state-of-the-art systems biology approaches, we will look at molecular mechanisms underlying breast cancer development. This work will aid in early detection of breast cancer as well as provide important biomarkers for therapeutic and diagnostic applications.
- Proteomic characterization of pancreatic cancer. Major advances in cancer control will be greatly aided by early detection so as to diagnose and treat cancer in its pre-invasive state prior to metastasis. Unfortunately, for pancreatic cancer, the fourth leading cause of cancer-related death in the United States, effective early detection and screening are currently not available and tumors are typically diagnosed at a late stage, frequently after metastasis. Several promising new technologies are currently available which allow for the characterization of molecular changes associated with tumor initiation and progression. Our laboratory is presently characterizing biologically and clinically relevant pancreatic cancer biomarkers, using state-of-the-art proteomics and metabolomics as our discovery platform. These biomarkers are being characterized for therapeutic and/or diagnostic applications.
- Zhao J, Chang AC, Li C, Shedden KA, Thomas DG, Misek DE, Giordano TJ, Beer DG and Lubman DM. Comparative proteomic analysis of Barrett metaplasia and esophageal adenocarcinomas using 2-D liquid mass mapping. Mol. Cell. Proteomics, 6:987-999, 2007.
- Zhao J, Patwa TH, Qiu W, Shedden K, Hinderer R, Misek DE, Anderson MA, Simeone DM and Lubman DM. Glycoprotein microarrays with multi-lectin detection: unique lectin binding patterns as a tool for classifying normal, chronic pancreatitis and pancreatic cancer sera. J. Proteome Research, 6:1864-1874, 2007.
- Wu R, Hendrix-Lucas N, Kuick R, Zhai Y, Schwartz DR, Akyol A, Hanash S, Misek DE, Katabuchi H, Williams BO, Fearon ER and Cho KR. Mouse Model of Human Ovarian Endometrioid Adenocarcinoma Based on Somatic Defects in the Wnt/β-catenin and PI3K/Pten Signaling Pathways. Cancer Cell, 11:321-333, 2007.
- Faca V, Song K, Wang H, Zhang Q, Krasnoselsky A, Newcomb LF, Plentz R, Gurumurthy S, Redston MS, Pitteri SJ, Pereira-Faca SR, Ireton RC, Katayama H, Glukhova V, Phanstiel D, Brenner DE, Anderson MA, Misek D, Scholler N, Urban ND, Barnett MJ, Edelstein C, Goodman GE, Thornquist MD, McIntosh M, DePinho RA, Bardeesy N and Hanash SM. A Mouse to Human Search for Plasma Proteome Changes Associated with Pancreatic Tumor Development. PLoS Med. 5:953-967, 2008.
- Kim H, Wu R, Cho KR, Thomas DG, Gossner G, Liu JR, Giordano TJ, Shedden KA, Misek DE, Lubman DM. Comparative proteomic analysis of low stage and high stage endometrioid ovarian adenocarcinomas. Proteomics- Clinical Applications, 2:571-584, 2008.
- Qiu Y, Patwa TH, Xu L, Shedden K, Misek DE, Tuck M, Jin G, Ruffin MT, Turgeon DK, Synal S, Bresalier R, Marcon N, Brenner DE, Lubman DM. Plasma Glycoprotein Profiling for Colorectal Cancer Biomarker Identification by Lectin Glycoarray and Lectin Blot. J. Proteome Res., 7:1693-1703, 2008.
- Shedden K, Taylor JMG, Enkemann SA, Tsao MS, Yeatman TJ, Gerald WL, Eschrich S, Jurisica I, Giordano TJ, Misek DE, Chang AC, Zhu CQ, Strumpf D, Hanash S, Shepherd F, Ding K, Seymour L, Naoki K, Pennell N, Weir B, Verhaak R, Ladd-Acosta C, Golub T, Gruidl M, Sharma A, Szoke J, Zakowski M, Rusch V, Kris M, Viale A, Motoi N, Travis W, Conley B, Seshan VE, Meyerson M, Kuick R, Dobbin KK, Lively T, Jacobson JW, Beer DG,. Gene Expression-Based Survival Prediction in Lung Adenocarcinoma: A Multi-Site, Blinded Validation Study. Nature Medicine, 14:822-827, 2008.
- Paczesny S, Krijanovski O, Braun TM, Choi S, Clouthier SG, Kuick R, Misek DE, Cooke KR, Kitko CL, Weyand A, Bickley D, Jones D, Whitfield J, Levine JE, Hanash SM and Ferrara JLM. A biomarker panel of acute graft versus host disease. Blood, 113:273-278, 2009.
- Vilar E, Mukherjee B, Kuick R, Raskin L, Misek DE, Taylor JMG, Giordano TJ, Hanash SM, Fearon ER, Rennert G, Gruber SB. Gene Expression Patterns in Mismatch Repair-Deficient Colorectal Cancers Highlight the Potential Therapeutic Role of Inhibitors of the PI3K-AKT-mTOR pathway. Clin. Cancer Res., 15:2829-2839, 2009.
- Dai L, Li C, Shedden KA, Misek DE and Lubman DM. Comparative Proteomic Study of Two Closely Related Ovarian Endometrioid Adenocarcinoma Cell Lines using cIEF Fractionation and Pathway Analysis. Electrophoresis, 30:1119-1131, 2009.
- Wang Y, Wu R, Cho KR, Thomas DG, Gossner G, Liu JR, Giordano TJ, Shedden KA, Misek DE, Lubman DM. Differential Protein Mapping of Ovarian Serous Adenocarcinomas: Identification of Potential Markers for Distinct Tumor Stage. J. Prot. Res., 8:1452-1463, 2009.