Biology and Genetics of Metastatic Disease My laboratory studies the molecular alterations that contribute to metastasis formation, a poorly understood process and primary cause of solid cancer deaths. It has long been thought that metastasis is caused by somatic metastasis driver mutations—postulated alterations that have yet to be identified. By showing that levels of specific microRNAs become altered in metastatic tumors and identifying their target genes, my lab identified and characterized critical pathways and processes underlying metastasis formation. By studying germline variants of one such target metastasis gene, we discovered that metastatic potential can also pre- date tumor formation and be genetically inherited—revealing an unanticipated genetic underpinning for metastasis and opening up a new direction for the field. Specifically, we determined that two common human germline variants of the secreted glycoprotein ApoE promote or suppress metastasis in melanoma, with recent data suggesting this principle may apply to additional cancers. ApoE signaling was found to govern vascular and immune interactions as well as cellular invasiveness that collectively contribute to metastasis formation. These insights have significant translational potential and formed the basis of clinical trials that are providing proof-of-concept for ‘metastasis targeting therapy’, where multiple metastasis regression responses were observed in advanced stage patients for whom standard of care and immunotherapy treatments had failed. Going forward, we will use allelic variants of ApoE as powerful genetic entry points to understand the molecular events underlying metastasis formation, where we will define how ApoE signals are received by cells and how ApoE mediates intracellular events. We will also extend the concept of hereditary metastasis genetics to additional cancers and genes, applying our reverse genetic and mouse modeling approaches to breast and colorectal cancer metastasis. To achieve this understanding, we will employ innovative optical, physiological, genetic modeling and screening methods to interrogate mouse and human metastatic transitions. This award will enable our group to establish the first genetically guided framework for understanding the molecular mechanisms governing metastasis formation—enabling new avenues for its therapeutic treatment and prevention.