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

Knelson, EH, Gaviglio, AL, Tewari, AK, Armstrong, MB, Mythreye, K, and Blobe, GC. "Type III TGF-β receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma." J Clin Invest 123, no. 11 (November 2013): 4786-4798.

PMID
24216509
Full Text

Hanks, BA, Holtzhausen, A, Evans, KS, Jamieson, R, Gimpel, P, Campbell, OM, Hector-Greene, M, Sun, L, Tewari, A, George, A, Starr, M, Nixon, A, Augustine, C, Beasley, G, Tyler, DS, Osada, T, Morse, MA, Ling, L, Lyerly, HK, and Blobe, GC. "Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment." J Clin Invest 123, no. 9 (September 2013): 3925-3940.

PMID
23925295
Full Text

Uronis, HE, Cushman, SM, Bendell, JC, Blobe, GC, Morse, MA, Nixon, AB, Dellinger, A, Starr, MD, Li, H, Meadows, K, Gockerman, J, Pang, H, and Hurwitz, HI. "A phase I study of ABT-510 plus bevacizumab in advanced solid tumors." Cancer Med 2, no. 3 (June 2013): 316-324.

PMID
23930208
Full Text

Knelson, EH, Gaviglio, AL, Tewari, AK, Armstrong, MB, Nixon, AB, Starr, MD, Mythreye, K, and Blobe, GC. "Abstract 5041: The type III TGF-beta receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma." April 15, 2013.

Full Text

Mythreye, K, Knelson, EH, Gatza, CE, Gatza, ML, and Blobe, GC. "TβRIII/β-arrestin2 regulates integrin α5β1 trafficking, function, and localization in epithelial cells." Oncogene 32, no. 11 (March 14, 2013): 1416-1427.

PMID
22562249
Full Text

Blobe, GC, Meyer, AE, Mythreye, K, Meyer, AE, Mythreye, K, and Blobe, GC. "Emerging roles of TGF-β co-receptors in human diseaseEmerging roles of TGF-β co-receptors in human disease (PublishedPublished)." In TGF-B in Human Disease, 59-89. January 1, 2013.

Full Text

Osborne, LD, Li, G, O'Brien, E, Blobe, GC, Superfine, R, and Mythreye, K. "TGF-beta regulates the Rho GEFs LARG and GEF-H1 during EMT to impact stiffening response to force and cell invasion." MOLECULAR BIOLOGY OF THE CELL 24 (2013).

Scholars@Duke

Uronis, HE, Bendell, JC, Altomare, I, Blobe, GC, Hsu, SD, Morse, MA, Pang, H, Zafar, SY, Conkling, P, Favaro, J, Arrowood, CC, Cushman, SM, Meadows, KL, Brady, JC, Nixon, AB, and Hurwitz, HI. "A phase II study of capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas." Oncologist 18, no. 3 (2013): 271-272.

PMID
23485624
Full Text

Mythreye, K, Knelson, EH, Gatza, CE, Gatza, ML, and Blobe, GC. "TβRIII/β-arrestin2 regulates integrin α5β1 trafficking, function, and localization in epithelial cells." Oncogene 32, no. 11 (2013): 1416-1427.

Full Text

Oh, SY, Knelson, EH, Blobe, GC, and Mythreye, K. "The type III TGFβ receptor regulates filopodia formation via a Cdc42-mediated IRSp53-N-WASP interaction in epithelial cells." Biochemical Journal 454, no. 1 (2013): 79-89.

PMID
23750457
Full Text

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