Abstract
The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging. We integrate experiments and theory to determine the trajectories that single BRAFV600E mutant melanoma cancer cells take between drug-naive and drug-tolerant states. Although single-cell omics tools can yield snapshots of the cell-state landscape, the determination of individual cell trajectories through that space can be confounded by stochastic cell-state switching. We assayed for a panel of signaling, phenotypic, and metabolic regulators at points across 5 days of drug treatment to uncover a cell-state landscape with two paths connecting drug-naive and drug-tolerant states. The trajectory a given cell takes depends upon the drug-naive level of a lineage-restricted transcription factor. Each trajectory exhibits unique druggable susceptibilities, thus updating the paradigm of adaptive resistance development in an isogenic cell population.
Highlights
The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging
The design of this panel was informed by transcriptomic analysis of BRAFi-treated M397 cells (Supplementary Fig. 1) and existing literature[9,10,12,20,45]
Single-cell omics tools have proven immensely valuable for resolving the cellular heterogeneity of tissues at a single given time point, here we sought to quantitatively connect that cellular heterogeneity to dynamic heterogeneity of cell-state changes
Summary
The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging. Capturing the trajectories that individual cells take as they traverse those landscapes is challenging, even for the case of an isogenic cell line This is because multiplex single-cell omics methods only provide snapshots of the occupied cell-state space at a given instant. Under BRAF inhibition, these highly plastic cells rapidly transit from a drug-responsive state to a drug-tolerant state[10,16] We characterize this transition using integrated single-cell functional proteomic and metabolic assays designed to broadly sample proteins and metabolites associated with selected cancer hallmarks and cell-state-specific processes. The two trajectories are associated with distinct signaling and metabolic networks, and are independently druggable This finding challenges the current paradigm of targeted inhibitor resistance development and provides guidelines for assessing the value of combination therapies
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