Gerard Conrad Blobe, MD, PhD

Professor of Medicine
Professor of Pharmacology and Cancer Biology
Associate of the Duke Initiative for Science & Society
Member of the Duke Cancer Institute
Campus mail B354 Levine Science Research Center, 450 Research Drive, Durham, NC 27708
Phone (919) 668-6688

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.

In Their Words

Education and Training

  • Adult Oncology Fellow, Medicine, Dana Farber Cancer Institute, 1997 - 2000
  • Medical Resident, Medicine, Brigham and Women's Hospital, 1995 - 1997
  • Ph.D., Duke University, 1995
  • M.D., Duke University, 1995

Publications

Gordon, KJ, Kirkbride, KC, How, T, and Blobe, GC. "Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2." Carcinogenesis 30, no. 2 (February 2009): 238-248.

PMID
19056927
Full Text

Finger, EC, Lee, NY, You, H-J, and Blobe, GC. "Endocytosis of the type III transforming growth factor-beta (TGF-beta) receptor through the clathrin-independent/lipid raft pathway regulates TGF-beta signaling and receptor down-regulation." J Biol Chem 283, no. 50 (December 12, 2008): 34808-34818.

PMID
18845534
Full Text

Lee, NY, Ray, B, How, T, and 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 283, no. 47 (November 21, 2008): 32527-32533.

PMID
18775991
Full Text

Hempel, N, How, T, Cooper, SJ, Green, TR, Dong, M, Copland, JA, Wood, CG, and Blobe, GC. "Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta." Carcinogenesis 29, no. 5 (May 2008): 905-912.

PMID
18299279
Full Text

Gordon, KJ, and Blobe, GC. "Role of transforming growth factor-beta superfamily signaling pathways in human disease." Biochim Biophys Acta 1782, no. 4 (April 2008): 197-228. (Review)

PMID
18313409
Full Text

Kirkbride, KC, Townsend, TA, Bruinsma, MW, Barnett, JV, and Blobe, GC. "Bone morphogenetic proteins signal through the transforming growth factor-beta type III receptor." J Biol Chem 283, no. 12 (March 21, 2008): 7628-7637.

PMID
18184661
Full Text

Finger, EC, Turley, RS, Dong, M, How, T, Fields, TA, and Blobe, GC. "TbetaRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity." Carcinogenesis 29, no. 3 (March 2008): 528-535.

PMID
18174241
Full Text

Gordon, KJ, Dong, M, Chislock, EM, Fields, TA, and 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 29, no. 2 (February 2008): 252-262.

PMID
17999987
Full Text

You, HJ, Bruinsma, MW, How, T, Ostrander, JH, and 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 28, no. 12 (December 2007): 2491-2500.

PMID
17768179
Full Text

Lee, NY, and 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 282, no. 29 (July 20, 2007): 21507-21517.

PMID
17540773
Full Text

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