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 (TßRIII)  as a critical mediator/regulator of TGF-ß signaling. Specifically we have demonstrated that regulating TßRIII expression levels is sufficient to regulate TGF-ß signaling, and that decreased TßRIII expression is a common phenomenon in human cancers, resulting in cancer progression. TßRIII is also shed from the surface to generate soluble TßRIII, which we have demonstrated has a role in creating an immunotolerant tumor microenvironment. The role of TßRIII and soluble TßRIII in the tumor immune microenvironment is currently being investigated using a multidisciplinary approach.

Activin receptor-like kinase 4 (ALK4) is a type I transforming growth factor-β (TGF-β) superfamily receptor that mediates signaling for several TGF-β superfamily ligands, including activin, Nodal and GDF5. We have demonstrated that mutation or copy number loss of ALK4 occurs in 35% of pancreatic cancer patients, with loss of ALK4 expression associated with a poorer prognosis. ALK4 has also been identified in an unbiased screen as a gene whose disruption enhances Ras mediated pancreatic tumorigenesis in vivo. We have demonstrated that loss of ALK4 expression increases canonical TGF-β signaling to increase cancer invasion and metastasis in vivo. We are currently investigating the mechanism by which loss of ALK4 regulates TGF-β signaling, how it may effect other signaling pathways, and how to use this knowledge to treat pancreatic cancer patients with loss of ALK4 function.

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

Ehanire, Tosan, Licheng Ren, Jennifer Bond, Manuel Medina, George Li, Latif Bashirov, Lei Chen, et al. “Erratum to: angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction..” J Mol Med (Berl), March 2015. https://doi.org/10.1007/s00109-015-1262-6.

PMID
25676696
Full Text

Osborne, Lukas D., George Z. Li, Tam How, E Tim O’Brien, Gerard C. Blobe, Richard Superfine, and Karthikeyan Mythreye. “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): 3528–40. https://doi.org/10.1091/mbc.E14-05-1015.

PMID
25143398
Full Text

Hector-Greene, Melissa E., and Gerard C. Blobe. “The role of type III TGF-beta receptor in tumor angiogenesis.” Angiogenesis 17, no. 4 (October 1, 2014): 963–963.

Scholars@Duke

Knelson, Erik H., Angela L. Gaviglio, Jasmine C. Nee, Mark D. Starr, Andrew B. Nixon, Stephen G. Marcus, and Gerard C. Blobe. “Abstract 2674: Stroma biology identifies heparins as differentiating agents in neuroblastoma.” In Experimental and Molecular Therapeutics. American Association for Cancer Research, 2014. https://doi.org/10.1158/1538-7445.am2014-2674.

Full Text

Liu, Yingmiao, Hongyu Tian, Gerard C. Blobe, Charles P. Theuer, Herbert I. Hurwitz, and Andrew B. Nixon. “Effects of the combination of TRC105 and bevacizumab on endothelial cell biology..” Invest New Drugs 32, no. 5 (October 2014): 851–59. https://doi.org/10.1007/s10637-014-0129-y.

PMID
24994097
Full Text

Meyer, Alison E., Catherine E. Gatza, Tam How, Mark Starr, Andrew B. Nixon, and Gerard C. Blobe. “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. https://doi.org/10.1091/mbc.E14-03-0825.

PMID
24870032
Full Text

Elderbroom, Jennifer L., Jennifer J. Huang, Catherine E. Gatza, Jian Chen, Tam How, Mark Starr, Andrew B. Nixon, and Gerard C. Blobe. “Ectodomain shedding of TβRIII is required for TβRIII-mediated suppression of TGF-β signaling and breast cancer migration and invasion..” Molecular Biology of the Cell 25, no. 16 (August 2014): 2320–32. https://doi.org/10.1091/mbc.E13-09-0524.

PMID
24966170
Full Text

Knelson, Erik H., Angela L. Gaviglio, Jasmine C. Nee, Mark D. Starr, Andrew B. Nixon, Stephen G. Marcus, and Gerard C. Blobe. “Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth..” The Journal of Clinical Investigation 124, no. 7 (July 2014): 3016–31. https://doi.org/10.1172/JCI74270.

PMID
24937430
Full Text

Gatza, Catherine E., Jennifer L. Elderbroom, Sun Young Oh, Mark D. Starr, Andrew B. Nixon, and Gerard C. Blobe. “The balance of cell surface and soluble type III TGF-β receptor regulates BMP signaling in normal and cancerous mammary epithelial cells..” Neoplasia (New York, N.Y.) 16, no. 6 (June 2014): 489–500. https://doi.org/10.1016/j.neo.2014.05.008.

PMID
25077702
Full Text

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