Transforming growth factor- (TGF-) signaling has important roles in tumor progression and angiogenesis. In most human cancers, loss of expression of the type III TGF- receptor (TRIII), a TGF- superfamily co-receptor, correlates with increased angiogenesis, tumor growth and metastatic potential. Despite these observations, how TRIII controls angiogenesis remains unknown. Our lab has recently observed that vascular endothelial cells express TRIII. Moreover, we have established that TRIII forms stable complexes with Activin receptor-Like Kinase 1 (ALK1), an endothelium-specific TGF- superfamily receptor. ALK1 stimulation by bone morphogenetic protein 9 (BMP9) leads to activation of Smad 1/5/8 transcription factors, promoting angiogenesis. A fundamental knowledge gap in the field is the mechanism by which TRIII affects ALK1 signaling and whether TRIII promotes ALK1-mediated angiogenesis. Based on preliminary data, we propose the following hypothesis: TRIII is a co-receptor for ALK1, with BMP9 stimulating TRIII/ALK1 complex formation and internalization, leading to increased Smad1/5/8 signaling and increased tumor angiogenesis. This hypothesis will be addressed by three specific aims:
Aim 1. Determine whether TRIII binds ALK1 in a BMP9-dependent manner to promote TRIII/ALK1 complex internalization and Smad phosphorylation in endothelial cells.
Aim 2. Determine whether TRIII enhances angiogenesis in an ALK1-dependent manner.
Aim 3. Determine whether endothelial TRIII promotes tumor angiogenesis in an ALK1- dependent manner in vivo. These studies will uncover a novel role for TRIII in angiogenesis, elucidate mechanisms of cancer progression, and potentially provide mechanistic insight into the toxicity of anti-TGF- receptor based targeted therapies.
Patients with advanced-stage breast cancer have benefited from anti-angiogenic treatments, which slow tumor growth and dissemination by obliterating tumor-associated blood vessels. Unfortunately, the clinical utility of this treatment strategy has been hampered by emerging drug resistance and incomplete understanding of mechanisms of tumor angiogenesis and resistance to anti-angiogenesis therapy. Thus, these studies, where we investigate the role of TGF- superfamily receptors TRIII and ALK1 in tumor angiogenesis, are important to perform and relevant to public health, as these mechanistic insights will define biological functions of TRIII and ALK1 in the context of tumor angiogenesis, possibly leading to identification of novel biomarkers and therapeutic strategies. These studies could also provide a mechanism for resistance to current anti-angiogenesis targeted therapy.
