Research Synopsis    |    Role of TGF-β in Human Malignancy    |    Lab Funding

Research Synopsis

Our laboratory focuses on transforming growth factor-β (TGF-β) superfamily signal transduction pathways, and specifically, the role of these pathways in cancer biology. The TGF-β superfamily of polypeptide growth factors (including TGF-β, BMPs, activin/inhibin and GDFs) regulate growth, differentiation and morphogenesis in a cell and context specific manner. TGF-β and the TGF-β 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, see Figure). This dichotomy of TGF-β function remains a fundamental problem in the field both in terms of understanding the mechanism of action of the TGF-β 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-β is also a common feature of epithelial-derived human cancers (breast, colon, lung, pancreatic, prostate), however, mechanisms for TGF-β resistance remain undefined in the majority of cases. TGF-β 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 defined the type III TGF-β receptor (TβRIII), a co-receptor in the pathway, as a critical mediator/regulator of TGF-β signaling. Specifically we and others have demonstrated that regulating TbRIII expression is sufficient to regulate TGF-β signaling, and that TbRIII is a suppressor of cancer progression in most human cancers. The role of TbRIII and TbRIII-interacting proteins in TGF-β superfamily signaling, 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-β and the TGF-β signaling pathway also have an important role in vascular biology. Indeed, mutations in two endothelial specific TGF-β receptors, endoglin (a TGF-β superfamily co-receptor) and ALK-1 (a type I receptor in the TGF-β superfamily), 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. Despite the importance of these receptors, the signaling pathway downstream of endoglin and ALK-1 are unknown. Our laboratory has identified regulators of ALK-1 signaling, as well as novel mechanisms by which endoglin regulates Smad and non-Smad signaling. 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 pathway for the chemoprevention or treatment of human cancers.