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

Pomeraniec, L, Hector-Greene, M, Ehrlich, M, Blobe, GC, and Henis, YI. "Regulation of TGF-β receptor hetero-oligomerization and signaling by endoglin." Molecular biology of the cell 26, no. 17 (September 2015): 3117-3127.

PMID
26157163
Full Text

Ehanire, T, Ren, L, Bond, J, Medina, M, Li, G, Bashirov, L, Chen, L, Kokosis, G, Ibrahim, M, Selim, A, Blobe, GC, and Levinson, H. "Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction." March 2015.

PMID
25345602
Full Text

Ehanire, T, Ren, L, Bond, J, Medina, M, Li, G, Bashirov, L, Chen, L, Kokosis, G, Ibrahim, M, Selim, A, Blobe, GC, and Levinson, H. "Erratum to: angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction." Journal of molecular medicine (Berlin, Germany) 93, no. 3 (March 2015): 303-.

PMID
25676696
Full Text

Ehanire, T, Ren, L, Bond, J, Medina, M, Li, G, Bashirov, L, Chen, L, Kokosis, G, Ibrahim, M, Selim, A, Blobe, GC, and Levinson, H. "Erratum to Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction (J Mol Med, (2015), 10.1007/s00109-014-1211-9)." Journal of Molecular Medicine 93, no. 3 (February 19, 2015): 303-.

Full Text

Ehanire, T, Ren, L, Bond, J, Medina, M, Li, G, Bashirov, L, Chen, L, Kokosis, G, Ibrahim, M, Selim, A, Blobe, GC, and Levinson, H. "Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction." Journal of Molecular Medicine 93, no. 3 (February 19, 2015): 289-302.

Full Text

Osborne, LD, Li, GZ, How, T, O'Brien, ET, Blobe, GC, Superfine, R, and Mythreye, K. "TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion." Molecular biology of the cell 25, no. 22 (November 2014): 3528-3540.

PMID
25143398
Full Text

Knelson, EH, Gaviglio, AL, Nee, JC, Starr, MD, Nixon, AB, Marcus, SG, and Blobe, GC. "Abstract 2674: Stroma biology identifies heparins as differentiating agents in neuroblastoma." October 1, 2014.

Full Text

Liu, Y, Tian, H, Blobe, GC, Theuer, CP, Hurwitz, HI, and Nixon, AB. "Effects of the combination of TRC105 and bevacizumab on endothelial cell biology." Investigational new drugs 32, no. 5 (October 2014): 851-859.

PMID
24994097
Full Text

Hector-Greene, ME, and Blobe, GC. "The role of type III TGF-beta receptor in tumor angiogenesis." ANGIOGENESIS 17, no. 4 (October 2014): 963-963.

Scholars@Duke

Meyer, AE, Gatza, CE, How, T, Starr, M, Nixon, AB, and Blobe, GC. "Role of TGF-β receptor III localization in polarity and breast cancer progression." Molecular biology of the cell 25, no. 15 (August 2014): 2291-2304.

PMID
24870032
Full Text

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