Research synopsis:

Our laboratory focuses on transforming growth factor-beta (TGF-beta) superfamily signal transduction pathways, and specifically, the role of these pathways in cancer biology. The TGF-beta superfamily of polypeptide growth factors (including TGF-beta, BMPs, activin/inhibin and GDFs) regulate growth, differentiation and morphogenesis in a cell and context specific manner. TGF-beta and the TGF-beta 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-beta function remains a fundamental problem in the field both in terms of understanding the mechanism of action of the TGF-beta 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-beta is also a common feature of epithelial-derived human cancers (breast, colon, lung, pancreatic, prostate), however, mechanisms for TGF-beta resistance remain undefined in the majority of cases. TGF-beta 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-beta receptor (TbetaRIII), a co-receptor in the pathway, as a critical mediator/regulator of TGF-beta signaling. Specifically we and others have demonstrated that regulating TbetaRIII expression is sufficient to regulate TGF-beta signaling, and that TbetaRIII is a tumor suppressor in most human cancers. The role of TbetaRIII and TbetaRIII-interacting proteins in TGF-beta 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-beta and the TGF-beta signaling pathway also have an important role in vascular biology. Indeed, mutations in two endothelial specific TGF-beta receptors, endoglin (a TGF-beta superfamily co-receptor) and ALK-1 (a type I receptor in the TGF-beta 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 is unknown. Our laboratory has identified the nuclear hormone receptor, LXR-beta, as a protein that binds to activated ALK-1, is phosphorylated by ALK-1 and modulates ALK-1 signaling, providing the first insight into the 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 TbRIII, including binding beta-arrestin2 to regulate ERK signaling and endothelial cell migration. 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-beta pathway for the chemoprevention or treatment of human cancers.

Role of TGF-beta in Human Malignancy. In normal, non-transformed cells, the TGF-beta ligand acting through the TGF-beta signaling pathway induces G1 cell cycle arrest to inhibit proliferation, induce differentiation, or promote apoptosis. During transformation into cancerous cells, various components of the TGF-beta signaling pathway are mutated, making the cancer cells resistant to the effects of the TGF-beta ligand. These TGF-beta resistant cancer cells, which proliferate in an unregulated manner, as well as the surrounding stromal cells (fibroblasts) then increase their production of the TGF-beta ligand. This TGF-beta, by acting on the surrounding stromal cells, immune cells, and endothelial and smooth muscle cells, results in enhanced immunosuppression and angiogenesis, as well as increased invasiveness of the tumor, allowing for enhanced tumor invasion and metastasis. Some of the dichotomous effects of TGF-beta also result from altered responsiveness of the tumor cells themselves, perhaps as they undergo epithelial to mesenchymal transition (EMT).