Metastatic disease, or the spread of cancer cells from invasive primary tumor to distal organs through vasculature or lymphatics is responsible for majority of patient deaths and remains a clinical challenge. Not all invasive tumors are metastatic, therefore defining the determinants of metastatic competence and identifying cancer patients likely to develop metastasis or have residual disease is critical for clinical management of disease. Intratumor heterogeneity, inability to precisely isolate tumor cells from the invasive front and limited access to clinical follow- up data present a major challenge to identify metastatic competency determinants. Invasive intravascular growth is observed in approximately 15% of ccRCC patients as tumor thrombus. This invasive tumor extension can be accurately identified using cross sectional imaging including computerized tomography and magnetic resonance imaging scans and is valuable for tumor staging. We investigated resected invasive primary tumors with clearly defined extension into the vasculature to identify ccRCC invasion and metastasis determinants. Approximately fifty percent of ccRCC patients with intravascular tumor extension develop metastasis post nephrectomy and treatment and have poor survival outcome. Comprehensive transcriptomic analysis of metastatic and non-metastatic invasive ccRCC tumors with intravascular extension identified metastatic competence determinants. Our central hypothesis is that metastatic competence of invasive ccRCC tumors is dependent on PRRX1 driven vasculogenic mimicry and the ability of chemotactic cytokines to recruit CXCR2 positive infiltrating immune cells to the invasive front that promote dissemination and colonization to distal organs. Pharmacologic and conditional genetic manipulation of PRRX1 and CXCL1 ligands in experimental model systems resulted in attenuated metastasis. We will investigate the role of PRRX1 mediated vasculogenic mimicry in driving metastasis and assess the impact of TGF-β inhibitor on metastatic progression. We will also elucidate the role of CXCL1 in driving metastasis and assess the impact of CXCR2 antagonist on metastatic progression. We anticipate this project will decipher pathophysiologic mechanisms determining metastatic competency of invasive ccRCC and develop innovative therapies to disrupt metastatic competence, which in combination with current standard of care regimens will result in effective management of metastatic disease.