
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
- Duke University, M.D. 1995
- Duke University, Ph.D. 1995
- Brigham and Women's Hospital, Medical Resident, Medicine
- Dana Farber Cancer Institute, Adult Oncology Fellow, Medicine
Selected Grants and Awards
- Role of ALK4 in Regulating Receptor Trafficking and Pancreatic Cancer Biology
- Role for TbetaRIII Shedding in the Tumor Microenvironment
- TGFBI in the breast cancer microenvironment promotes TGF-B signaling to increase tumor progression
- Medical Scientist Training Program
- Training Program in Developmental and Stem Cell Biology
- Utilizing Nucleic-Acid Scavengers to Ameliorate Inflammation-driven Metastatic Progression in Breast Cancer
- Utilizing Nucleic-Acid Scavengers to Ameliorate Inflammation-driven Metastatic Progression in Breast Cancer
- Translational Research in Surgical Oncology
- Translational Research in Surgical Oncology
- Melanoma-mediated Dendritic Cell Tolerization and Immune Evasion
- Organization and Function of Cellular Structure
- Organization and Function of Cellular Structure
- Pharmacological Sciences Training Program
- Pharmacology Industry Internships for Ph.D. Students
- UNC - Duke Immunotherapy Training Program
- Fibulin-3 as a Novel Biomarker and Trget in the Breast Tumor Microenvironment
- A Novel Function for ALK4 in Suppressing Breast Cancer Progression
- Dissecting ALK4 Function in Cancer Progression
- The Role of Type III TGF-beta Receptor in ALK1-mediated Tumor Angiogenesis
- Role of Type III TGF-beta Receptor Shedding in Lung Cancer Initiation and Progression
- Therapeutic Targeting of the TGF-BSignaling Axis to Modulate the Tumor Immune Microenvironment and Enhance Melanoma Immu
- Epigenetic Regulation of Neuroblast Differentiation
- Endoglin Regulates Biology and Signal Transduction in Vascular Smooth Muscle Cells
- 2014 Gertrude B. Elion Mentored Medical Student Research Award
- The Role of Type III TGF-beta Receptor in the Fibrotic Tumor Stroma
- Cancer Biology Training Grant
- Alex's Million Mile Unrestricted Grant
- Stroma Biology Identifies Heparin as a Differentiating Agent in Neuroblastoma
- JUN PROTEINS IN EPIDERMAL HOMEOSTASIS AND NEOPLASIA
- Function of TbRIII as a BMP Co-receptor in Human Cancer
- Role of TbRIII in Regulating Motility and Invasion
- Alternative splicing and epithelial-mesenchymal plasticity in prostate tumors
- Role of TGF beta Receptor III Localization in Breast Cancer Progression
- The Role of Stroma-derived Soluble TbetaRIII in Neuroblastoma
- Role of Type III TGF-b Receptor in Mediating Immunosuppression During Breast Cancer Progression
- Anti-VEGF in Tumors & Wounds: Efficacy vs Toxicity
- Elucidating the Role of T_RIII in Breast Carcinogenesis
- Endoglin Regulates Endothelial Survival and Capillary Tube Stability
- Multispectral Imaging Flow Cytometer Core
- Novel Roles for Endoglin in TGF-b Signaling
- Type III TGF-beta Receptor as a Mediator/Reg. of Sign
- Role of the TGF-Beta Receptor in Cancer Biology
- ALK-1 and Endoglin Signaling in Endothelial Cells
- Biomarker Studies for Novel Anti-Cancer Agents
- CLN3: Modulation of Apoptosis and Ceramide Levels
- Role of the Type III TGF-b Receptor in TGF-b Signaling