Optogenetic Control of Tumor Initiation and Tumor Progression in vivo

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Cancer research and therapy development rely heavily on animal models. One of the key features desired in a mouse model is ability to control tumor initiation and progression. However, existing methods cannot control where and when tumor will form and/or do not allow regulation of specific oncogenic signaling patterns driving tumor progression. Here we propose to develop an in vivo system that will provide tight control of oncogenic signaling with precise control of timing and location within a specific organ. To achieve spatial and temporal control of protein activity and gene expression we will use a novel optogenetic strategy that employs engineered light-regulated proteins. Our previous studies funded by an IMAT R21 grant allowed us to develop a Light- Regulated (LightR) domain that can function as allosteric switch to control protein activity. Using this method, we propose to develop in vivo strategy for regulation of oncogenic protein kinases and expression of oncogenes that drive initiation and progression of lung cancer as well as mediate development of metastatic lesions in the lung. The goal is to build a set of tools that will allow researcher to model oncogenic signaling in a specific organ and interrogate its role in tumor development and regulation of tumor environment. As model systems for development of new technology, we will develop a toolkit that enables regulation of oncogenic KRas expression and Src kinase activity at a selected location in mouse lungs with precise timing. These models will allow researchers to interrogate the role of KRas and Src in initiation of lung cancer, its progression, and spreading to other locations. We will also develop a system that will enable local regulation of oncogenic signaling promoting metastasis of circulating cancer cells in the lung. This method will enable regulation of specific stages of metastatic process. It will provide new tools for interrogation of oncogenic signaling in promoting metastatic ability of cancer cells and regulation of the pre-metastatic tumor niche in vivo. The design of the proposed systems will ensure their application for different cancer models.