Grant: Project Grant

Metastatic spread during which cancer cells leave primary tumor, enter the circulation, colonize and grow in distant tissues and organs represents the most significant challenge in clinical management of cancer patients and is a major cause of cancer-related deaths. Notwithstanding recent advances, the molecular mechanisms underpinning this process remain obscure. This substantially hampers the efforts to devise therapeutic approaches to target cancer metastasis. In this proposal, we will set out to address this major gap in knowledge by building up on our preliminary findings that suggested a central role of the cellular system that governs protein synthesis in metastasis. Specifically, we have identified a rheostat-like pathway that turns on and off translational machinery and fine-tunes cellular protein composition during different steps in metastatic cascade. We show that disrupting this mechanism effectively blocks breast cancer metastasis in mice and "metastatic"-like properties of human breast cancer cells. Based on this, we propose to dissect the mechanisms that underlie these phenomena and identify the components of this metastasis-driving translational rheostat. Results of this proposal are anticipated to provide molecular basis for devising better treatments for metastatic breast cancer.