Metastasis is the major cause of death in most cancers. Metastases result from cancer cells that have migrated away from the primary tumor and spread to other organs. This requires tumor cells to adapt by acquiring properties, unique from the primary tumor, to grow in their new surroundings. Thus, current therapies designed to treat primary tumors have limited efficacy in metastasis. A major barrier to understanding and targeting metastasis specific adaptations is the lack of model systems that capture the metastatic behaviors of human tumors. A powerful method to study tumor biology are genetically engineered mouse models (GEMMs). GEMMs rely on genetically encoded Cre-recombinase proteins t...

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Metastasis is the major cause of death in most cancers. Metastases result from cancer cells that have migrated away from the primary tumor and spread to other organs. This requires tumor cells to adapt by acquiring properties, unique from the primary tumor, to grow in their new surroundings. Thus, current therapies designed to treat primary tumors have limited efficacy in metastasis. A major barrier to understanding and targeting metastasis specific adaptations is the lack of model systems that capture the metastatic behaviors of human tumors. A powerful method to study tumor biology are genetically engineered mouse models (GEMMs). GEMMs rely on genetically encoded Cre-recombinase proteins to induce cancer formation by activating oncogenic mutations in murine cells. To generate tumors, Cre expression is controlled by specific promoters leading to mutations in the cells or tissue where these promoters are active. However, promoters driving Cre are often not specific to a given tissue or cell-type resulting in simultaneous primary tumor formation in many different organs which prevents assessment of metastasis. Thus, generating GEMMs where we can precisely activate tumor formation to a specific region of an organ can overcome these limitations and enable studies of metastasis in their native environments. In this proposal we develop a novel optogenetic system where Cre activation is driven by externally applied light beams, rather than non-specific promoters. The ability to target light mediated control of Cre at the sub-millimeter or single-cell level allows for precise oncogene activation to any cell-type or tissue region. This overcomes many of the limitations of existing GEMM tumor models and enables analysis of metastasis from different organs and cancer types. We will use this novel technology to study and define the molecular adaptations that arise in metastasis and identify new drug targets to treat metastatic GI tumors.

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