A Multimodal Framework to Uncover Drug-Responsive Subpopulations in Triple-Negative Breast Cancer.

Understanding how individual cancer cells adapt to drug treatment is a fundamental challenge limiting precision medicine cancer therapy strategies. While single-cell technologies have advanced our understanding of cellular heterogeneity, efforts to connect the behavior of individual cells to broader tumor drug responses and uncover global trends across diverse systems remain limited. There is a growing availability of single-cell and bulk omics data, but a lack of centralized tools and repositories makes it difficult to study drug response globally, especially at the level of single-cell adaptation. To address this, we present a multimodal framework that integrates bulk and single-cell treated and untreated transcriptomics data to identify drug responsive cell populations in triple-negative breast cancer (TNBC). Our framework leverages population-scale bulk transcriptomics data from TNBC samples to define seven main "identities", each representing unique combinations of biologically relevant genes. These identities are dynamic and trackable, allowing us to map them onto single cells and uncover global patterns of how cell populations respond to drug treatment. Unlike static classifications, this approach captures the evolving nature of cellular states, revealing that a select few identities dominate and drive population-level responses during treatment. Crucially, our ability to decode these trends through the inherent noise of single-cell data provides a clearer picture of how heterogeneous cell populations adapt to therapy. By identifying the dominant identities and their dynamics, we can better predict how entire tumors respond to treatment. This insight is essential for designing precise combination therapies tailored to the unique heterogeneity of patient tumors, addressing the single-cell variations that ultimately determine therapeutic outcomes.