The overarching goal of this application is to answer an important question in the field of cancer research, namely, how does the metastatic tumor environment evolve to enable immune evasion and metastatic outgrowth? We hypothesize that co-evolution between metastatic tumor cells and the metastatic environment - the metastatic niche - involves a highly plastic and continuous transcriptome trajectory. Defining this dynamic transcriptome trajectory over space and time during co-evolution of tumor and niche will lead to novel insights required to develop anti-cancer therapies that deliver more sustained control of tumor prog...

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The overarching goal of this application is to answer an important question in the field of cancer research, namely, how does the metastatic tumor environment evolve to enable immune evasion and metastatic outgrowth? We hypothesize that co-evolution between metastatic tumor cells and the metastatic environment - the metastatic niche - involves a highly plastic and continuous transcriptome trajectory. Defining this dynamic transcriptome trajectory over space and time during co-evolution of tumor and niche will lead to novel insights required to develop anti-cancer therapies that deliver more sustained control of tumor progression and metastasis than is currently achievable. Specifically, we will accomplish the following major goals: 1) Develop an in vivo lineage tracing system to genetically tag cells within the metastatic niche. Coupled with single-cell analysis methods, we will map the landscape of compositional and transcriptome dynamics within the niche. 2) Analyze the signaling trajectory that drives metastatic immune evasion via in vitro and in vivo perturbation screens. 3) Investigate the function and mechanisms of signaling nodes that potentially serve as novel immunotherapy targets for metastatic disease. The top-tier and highly collaborative research environment at the UT Southwestern Simmons Comprehensive Cancer Center, combined with its rich clinical patient resources will greatly facilitate our mechanistic studies of the highly plastic and co-evolving landscape of tumor cells and the metastatic niche.

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