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

Tian, H, Huang, JJ, Golzio, C, Gao, X, Hector-Greene, M, Katsanis, N, and Blobe, GC. "Endoglin interacts with VEGFR2 to promote angiogenesis." Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology 32, no. 6 (June 2018): 2934-2949.

PMID
29401587
Full Text

Tian, H, Ketova, T, Hardy, D, Xu, X, Gao, X, Zijlstra, A, and Blobe, GC. "Endoglin Mediates Vascular Maturation by Promoting Vascular Smooth Muscle Cell Migration and Spreading." Arteriosclerosis, thrombosis, and vascular biology 37, no. 6 (June 2017): 1115-1126.

PMID
28450296
Full Text

Gaviglio, AL, Knelson, EH, and Blobe, GC. "Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 31, no. 5 (May 2017): 1903-1915.

PMID
28174207
Full Text

Riedel, RF, Meadows, KL, Lee, PH, Morse, MA, Uronis, HE, Blobe, GC, George, DJ, Crawford, J, Niedzwiecki, D, Rushing, CN, Arrowood, CC, and Hurwitz, HI. "Phase I study of pazopanib plus TH-302 in advanced solid tumors." Cancer chemotherapy and pharmacology 79, no. 3 (March 2017): 611-619.

PMID
28238078
Full Text

Hesler, RA, Huang, JJ, Starr, MD, Treboschi, VM, Bernanke, AG, Nixon, AB, McCall, SJ, White, RR, and Blobe, GC. "TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3." Carcinogenesis 37, no. 11 (November 2016): 1041-1051.

PMID
27604902
Full Text

Huang, JJ, and Blobe, GC. "Dichotomous roles of TGF-β in human cancer." Biochemical Society Transactions 44, no. 5 (October 2016): 1441-1454. (Review)

PMID
27911726
Full Text

Gaviglio, AL, and Blobe, GC. "Abstract 1182: Heparin-binding epidermal growth factor-like growth factor is a pro-differentiating factor in neuroblastoma." July 15, 2016.

Full Text

Cribb, JA, Osborne, LD, Beicker, K, Psioda, M, Chen, J, O'Brien, ET, Taylor Ii, RM, Vicci, L, Hsiao, JP-L, Shao, C, Falvo, M, Ibrahim, JG, Wood, KC, Blobe, GC, and Superfine, R. "An Automated High-throughput Array Microscope for Cancer Cell Mechanics." Scientific reports 6 (June 6, 2016): 27371-.

PMID
27265611
Full Text

Tian, H, Liu, J, Chen, J, Gatza, ML, and Blobe, GC. "Fibulin-3 is a novel TGF-β pathway inhibitor in the breast cancer microenvironment." Oncogene 34, no. 45 (November 2015): 5635-5647.

PMID
25823021
Full Text

Tazat, K, Hector-Greene, M, Blobe, GC, and Henis, YI. "TβRIII independently binds type I and type II TGF-β receptors to inhibit TGF-β signaling." Molecular biology of the cell 26, no. 19 (October 2015): 3535-3545.

PMID
26269580
Full Text

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