Tracing cellular plasticity and emergent drug resistant fates in single cancer cells
Non-genetic drug resistance in clonal cells
Non-genetic heterogeneity within individual cancer cells can result in diverse paths to drug resistance. To trace this process, we have developed FateMap, a framework that combines high-throughput lineage barcoding, single cell profiling, and multiplexed single-molecule RNA FISH (Nature, 2023). FateMap enables us to catalog and track thousands of individual cancer cell lineages as they acquire diverse resistant fates upon exposure to therapy. We will adapt this multiscale framework to spatiotemporally reveal emergent heterogeneous fates and ecological principles regulating tumor progression.
Mathematical models of heritable transcriptional fluctuations underlying cellular memories
Heritable non-genetic fluctuations in rare subsets of cells can lead to biologically distinct behavior in cancer and stem cells. The unique rarity and long timescales of such single-cell variabilities make them conceptually distinct from the classically studied fluctuations, often dubbed as “noise”. Our recent theoretical work (Cell Systems, 2020) demonstrated that these heritable fluctuations can simply arise from genes stochastically interacting within a simplified network. We will build predictive mathematical models to identify the potential origins and nature of the transcriptional fluctuations that underlie cellular plasticity in various cancer and stem cell systems.
Engineering plasticity and fate decisions in ex vivo models of development
Ex vivo 3D culture systems mimicking mammalian development have emerged as tractable models to study fundamental questions surrounding state transitions and fate choices in development. By combining quantitative imaging, lineage tracing, optogenetics, biophysical modeling, and microengineered devices, we will establish synthetic quantitative frameworks to 1. “reassemble” early mammalian development; 2. decipher spatiotemporal effects of pathogenic mutations on fate choices and tissue organization.
We thank the following organizations for their recently concluded and current support of our research work:
