UC San Diego

Advances in high-throughput sequencing and spatial profiling technologies have enabled unprecedented characterization of tumor biology; however, most approaches interrogate tumor-intrinsic programs, the tumor microenvironment, and systemic immunity in isolation, limiting mechanistic understanding of therapeutic response. In this dissertation, we develop an integrative, multi-scale framework to define tumor ecosystem states that capture the coordinated interactions between malignant cells, stromal compartments, and immune populations across molecular, spatial, and systemic levels. Using bulk RNA sequencing of triple-negative breast cancer (TNBC) tumors, we identify three reproducible tumor ecosystem states (subtypes) defined by distinct combinations of epithelial, immune, and stromal programs. These subtypes are associated with differential survival outcomes and are governed by subtype-specific regulatory networks, including interferon-driven immune activation, stromal fibrosis and hypoxia, and transcriptional plasticity linked to nuclear receptor signaling, epithelial-to-mesenchymal transition, and metabolic reprogramming. Notably, we identify a TNBC subtype characterized by elevated estrogen receptor (ESR1) mRNA expression despite the absence of protein expression, associated with inflammatory and lipid signaling pathways and recurrent sequence variants, suggesting a non-canonical regulatory mechanism. To resolve how these subtypes are organized within tissue, we integrate spatial transcriptomics and multiplexed imaging, revealing that tumor-intrinsic and microenvironmental programs are spatially compartmentalized across epithelial and stromal regions. These spatial architectures govern immune engagement, stromal interactions, and invasive behavior. Complementary analysis of peripheral blood mononuclear cells further reveals that coordinated adaptive and innate immune dynamics distinguish therapeutic response, with pre-existing immune priming and effector activity associated with response, and persistent immune dysregulation and myeloid remodeling underlying resistance. Finally, we extend this framework to hepatoblastoma, demonstrating that therapeutic response is encoded in spatial tumor-microenvironment architectures, where relapse-prone tumors exhibit centralized, stromal-dominated niches driven by macrophage-fibroblast signaling, in contrast to immune-engaged, spatially distributed organization in non-relapse disease. Collectively, this work establishes a unified model in which tumor behavior emerges from spatially and systemically coordinated ecosystem states. These integrative frameworks provide a foundation for biomarker development and rational therapeutic stratification across heterogeneous solid tumors.