(CASI) Biochemical trajectories guiding rare cell plasticity and therapy resistance in single cancer cells

Project: Research project

Project Details

Description

Predicting the nature and consequences of this emerging heterogeneity as well as identifying its determinants is key to overcoming therapy resistance. However, this goal has proven difficult to accomplish, even in well-controlled systems, as the current methods of manually isolating resistant populations are imprecise, unscalable, and only provide a static view of the bulk properties of resistant fates. I have successfully developed FateMap, a combined scRNAseq and DNA barcoding system that follows the fates of hundreds of individual cancer cell clones and their progeny as they acquire resistance in response to targeted therapy. In Aim 1, I will use FateMap to not only systematically catalog the possible space of resistant fates, but also map the fate lineages to their original primed cell states preceding drug exposure. Furthermore, I will identify whether the state-to-fate relationships depends on the drug type and dosage, and if so, in what way. In Aim 2, I will develop experimental and computational approaches to retrospectively identify and measure the signaling and expression programs in the primed cell states that ultimately lead to distinct fates. This newfound ability will provide a dynamic view of the progression of a rare cell from a primed state to the resistant fate. In Aim 3, I will develop scalable functional assays to connect the ecosystem of resistant fates with their respective functions. Beyond 2D cell culture systems, I will determine the spatiotemporal organization of resistant fates in 3D assays and in vivo—this may reveal possible ecological and self-organizational principles regulating tumor progression and function.
StatusActive
Effective start/end date2/1/221/31/27

Funding

  • Burroughs Wellcome Fund (REQUEST ID #: 1020614.01)

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