Gerard C. Blobe, MD, PhD

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Services

• Esophageal Cancer
• Gastrointestinal Cancer

Department / Division:
Medicine / Medical Oncology

Address:
Box 91004
Durham, NC 27708

Appointment Telephone:
919-668-6688

Office Telephone:
919-668-1352

Fax Telephone:
919-681-6906

• MD, Duke University School of Medicine, 1995

• Internal Medicine, Brigham and Women's Hospital (Massachusetts), 1995-1997
• Medical Oncology, Dana Farber Cancer Institute (Massachusetts), 1997-2000

• PhD, Cell Biology, Duke University, 1995

Clinical Interests:
Treatment of patients with colorectal and pancreatic cancer with emphasis on Phase I/Experimental Therapeutics

Research Interests:
Our laboratory focuses on transforming growth factor-ß (TGF-ß) superfamily signal transduction pathways, and specifically, the role of these pathways in cancer biology. The TGF-ß superfamily is comprised of a number of polypeptide growth factors, including  TGF-βs, bone morphogenetic proteins (BMPs) and activin) that regulate growth, differentiation and morphogenesis in a cell and context specific manner. TGF-ß and the TGF-ß signaling pathway have a dichotomous role in cancer biology, as both tumor-suppressor genes (presumably as regulators of cellular proliferation, differentiation and apoptosis) and as tumor promoters (presumably as regulators of cellular motility, adhesion, angiogenesis and the immune system). This dichotomy of TGF-ß function remains a fundamental problem in the field both in terms of understanding the mechanism of action of the TGF-ß pathway, and directly impacting our ability to target this pathway for the chemoprevention or treatment of human cancers. Resistance to the tumor suppressor effects of TGF-ß is also a common feature of epithelial-derived human cancers (breast, colon, lung, pancreatic, prostate), however, mechanisms for TGF-ß resistance remain undefined in the majority of cases. TGF-ß regulates cellular processes by binding to three high affinity cell surface receptors, the type I, type II, and type III receptors. Recent studies by our laboratory and others have established the type III TGF-ß receptor as a critical mediator/regulator of TGF-ß signaling. Specifically we have demonstrated that regulating type III TGF-ß receptor expression levels is sufficient to regulate TGF-ß signaling, and that decreased type III receptor expression is a common phenomenon in human cancers, resulting in cancer progression. The role of the type III TGF-ß receptor and type III TGF-ß receptor-interacting proteins in TGF-ß signaling and cancer biology and the epithelial to mesenchymal transition that occurs in human breast, colon and pancreatic cancers are currently being investigated using a multidisciplinary approach.
TGF-ß and the TGF-ß superfamily signaling pathways also have an important role in vascular biology. Indeed, mutations in two endothelial specific TGF-ß superfamily receptors, endoglin and ALK-1 (a type I receptor in the TGF-ß family), are responsible for the human vascular disease, hereditary hemorrhagic telangiectasia (HHT), and mice which lack expression of these receptors are embryonic lethal due to defects in angiogenesis. In addition, endoglin expression is potently up regulated during tumor-induced angiogenesis. In endothelial cells, TGF-ß signals through the type I TGF-ß receptor (ALK-5) or through ALK-1, to mediate opposing effects on endothelial cell proliferation and migration. However, the role of endoglin in regulating the balance in signaling between these pathways is unknown. Our laboratory has identified the nuclear hormone receptor, LXR-ß, as a protein that binds to activated ALK-1, is phosphorylated by ALK-1 and modulates ALK-1 signaling,establishing a novel signaling pathway downstream of ALK-1. Investigations in our laboratory have also revealed important functions for the cytoplasmic domain of endoglin, which is highly homologous to the cytoplasmic domain of the type III TGF-ß receptor. Studies are currently underway to further elucidate the signal transduction pathway downstream from these receptors and to establish their role in regulating tumor-induced angiogenesis. The ultimate goal of these studies is the ability to target the TGF-ß pathway for the chemoprevention or treatment of human cancers.
As endoglin and the type III TGF-ß receptors are both "co-receptors," a class of poorly understood cell surface receptors that bind ligand but are not thought to signal directly, another focus for the laboratory is establishing the role of these co-receptors in orchestrating signaling in physiological and pathophysiological settings.

Representative Publications:
Lee NY, Ray BN, How T, Blobe GC. Endoglin promotes transforming growth factor-beta -mediated smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC. J Biol Chem. 2008 Sep 5. (2008) Abstract

Kirkbride KC, Townsend TA, Bruinsma MW, Barnett JV, Blobe GC. Bone morphogenetic proteins signal through the transforming growth factor-beta type III receptor. J Biol Chem. 2008 Mar 21;283(12):7628-37. (2008) Abstract

Hempel N, How T, Cooper SJ, Green TR, Dong M, Copland JA, Wood CG, Blobe GC. Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta. Carcinogenesis. 2008 May;29(5):905-12. (2008) Abstract

Gordon KJ, Dong M, Chislock EM, Fields TA, Blobe GC. Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression. Carcinogenesis. 2008 Feb;29(2):252-62. (2008) Abstract

Finger EC, Turley RS, Dong M, How T, Fields TA, Blobe GC. TbetaRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity. Carcinogenesis. 2008 Mar;29(3):528-35. (2008) Abstract

Finger EC, Lee NY, You HJ, Blobe GC. Endocytosis of the type III TGF-beta receptor through the clathrin- independent/lipid raft pathway regulates TGF-beta signaling and receptor downregulation. J Biol Chem. 2008 Oct 8. (2008) Abstract

You HJ, Bruinsma MW, How T, Ostrander JH, Blobe GC. The type III TGF-{beta} Receptor Signals through both Smad3 and the p38 MAP Kinase Pathways to Contribute to Inhibition of Cell Proliferation. Carcinogenesis. 2007 Sep 3. (2007) Abstract

Turley RS, Finger EC, Hempel N, How T, Fields TA, Blobe GC. The type III transforming growth factor-beta receptor as a novel tumor suppressor gene in prostate cancer. Cancer Res. 2007 Feb 1;67(3):1090-8. (2007) Abstract

Lee NY, Blobe GC. The interaction of endoglin with beta-arrestin2 regulates transforming growth factor-beta-mediated ERK activation and migration in endothelial cells. J Biol Chem. 2007 Jul 20;282(29):21507-17. (2007) Abstract

Hempel N, How T, Dong M, Murphy SK, Fields TA, Blobe GC. Loss of betaglycan expression in ovarian cancer: role in motility and invasion. Cancer Res. 2007 Jun 1;67(11):5231-8. (2007) Abstract

Dong M, How T, Kirkbride KC, Gordon KJ, Lee JD, Hempel N, Kelly P, Moeller BJ, Marks JR, Blobe GC. The type III TGF-beta receptor suppresses breast cancer progression. J Clin Invest. 2007 Jan;117(1):206-17. (2007) Abstract

Kirkbride KC, Ray BN, Blobe GC. Cell-surface co-receptors: emerging roles in signaling and human disease. Trends Biochem Sci. 2005 Nov;30(11):611-21. (2005) Abstract

Elliott RL, Blobe GC. Role of transforming growth factor Beta in human cancer. J Clin Oncol. 2005 Mar 20;23(9):2078-93. (2005) Abstract

Chen W, Kirkbride KC, How T, Nelson CD, Mo J, Frederick JP, Wang XF, Lefkowitz RJ, Blobe GC. Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science. 2003 Sep 5;301(5638):1394-7. (2003) Abstract

Schiemann WP, Blobe GC, Kalume DE, Pandey A, Lodish HF. Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-beta and affects protein kinase cascades. J Biol Chem. 2002 Jul 26;277(30):27367-77. (2002) Abstract

Mo J, Fang SJ, Chen W, Blobe GC. Regulation of ALK-1 signaling by the nuclear receptor LXRbeta. J Biol Chem. 2002 Oct 18;():. (2002) Abstract

Blobe GC, Schiemann WP, Pepin MC, Beauchemin M, Moustakas A, Lodish HF, O'Connor-McCourt MD. Functional roles for the cytoplasmic domain of the type III transforming growth factor beta receptor in regulating transforming growth factor beta signaling. J Biol Chem. 2001 Jul 6;276(27):24627-37. (2001) Abstract

Blobe GC, Liu X, Fang SJ, How T, Lodish HF. A novel mechanism for regulating transforming growth factor beta (TGF-beta) signaling. Functional modulation of type III TGF-beta receptor expression through interaction with the PDZ domain protein, GIPC. J Biol Chem. 2001 Oct 26;276(43):39608-17. (2001) Abstract