Cancer metastasis plays an important role in determining long term patient prognosis and outcome. Many signaling pathways are involved in cancer leading to enhanced metastasis. Epithelial-to-mesenchymal transition (EMT) is an important step in the development of metastasis that enables tumor spread from its site of origin. TGFb is an important cytokine that plays a dual role in cancer progression. Initially, during the development of the primary tumor, TGFb is growth suppressive. However, during the process of tumor progression and especially during the later stages of metastasis development, TGFb plays a metastasis promoting role. Understanding the molecular mechanisms which leads to the switch of TGFb from a tumor suppressor to a metastasis promoter is vital to the development of novel therapies to target metastatic cancer. One of the key players shown to play an important role in cancer progression is integrin a3b1. Integrins are important cell adhesion molecules that mediate extracellular matrix adhesion, contribute to cellular signaling and promote cell migration. Integrins are implicated in tumor growth and cancer cell invasion from the primary tumor as well as tumor cell attachment at distant sites. In addition to playing a role in cancer cell adhesion, work performed in our laboratory has demonstrated that a3b1 can influence expression of several genes, such as MMP9 and Cox2, that are involved in EMT and angiogenesis. In addition, increases in MMP9 levels by TGFb require the expression of a3b1. It is highly probable that a3b1 is an important mediator for expression of other genes by TGFb that may help tumor growth and progression. This proposal will focus on using a variety of molecular biology techniques as well as in vivo mouse xenograft models to analyze interactions between a3b1 and TGFb receptor and determine how specific signaling pathways that are modulated by these interactions affect the metastatic process. The specific aims of this proposal are: Aim 1. To analyze coordinate roles of a3b1 and TGFb in regulating the expression of EMT-promoting genes such as Cox2. and Aim 2. To establish the role of a3b1 as a mediator of TGFb driven tumor growth and progression in an in vivo model system. The objectives for this proposal are to analyze signaling pathways and genes to identify targets of cancer metastasis that can lead to the development of novel therapies. Analyzing the interactions between TGFb receptor and a3b1 could lead to the identification of novel targets of cancer metastasis and provide an understanding of the molecular switch that promotes development of a malignant phenotype in response to TGFb signals. PUBLIC HEALTH RELEVANCE: This research project is focused on identifying key molecules and signaling pathways involved in the a3b1- dependent regulation of TGFb signaling leading to a pro-metastatic phenotype. These studies will contribute towards the understanding of malignant progression and lead to the development of novel therapies against metastatic cancer.