RESEARCH

Our lab studies how individual cells translate internal and external signals to decide on various outcomes such as growth, death, movement, or differentiation, with a focus on understanding how and why individuals in a population exhibit heterogeneous outcomes. Such heterogeneity is proposed to underlie complex biological responses such as acquisition of drug resistance and lineage specification during development. We use quantitative imaging to measure the changes in level, activity, or localization of proteins in single cells at high temporal resolution and correlate these behaviors with specific cell fates. Our goal is to use protein dynamics as a target for directing healthy and cancer cells towards specific cellular outcomes.

We focus on the signaling pathway governed by the tumor-suppressive transcription factor p53, which regulates cellular outcomes in response to a variety of cell stresses including DNA damage. p53 is the most commonly-mutated gene in cancer; more than half of all human cancers contain mutations in the p53 gene itself, and in almost all cancers the p53 regulatory circuit is functionally inactivated. We have found that p53 dynamics, i.e. changes in protein levels, help determine the final cellular outcomes following DNA damage. We use live single-cell imaging with fluorescently-labeled proteins to determine how the dynamic behavior is regulated, why different cells show different dynamical behaviors, and what consequences these behaviors have on cell survival. We apply similar quantitative single-cell approaches to study information processing in additional networks in human cells, including the networks controlling DNA repair, cell growth, and regulation of cell fate by the basic helix-loop-helix (bHLH) transcription factors.

Some of the questions we are currently investigating include:

-       What are the mechanisms by which cells sense and transmit information about DNA damage to p53?

-       What combination of p53 dynamics and p53 modifications triggers a given cell fate program?

-     How do p53 mutations influence its dynamic behavior to influence cell fate outcomes?

-       How do p53 dynamics lead to varying responses of different target genes?

-       How does the local cellular environment shape p53 dynamics?

In the long term, we are optimistic that these studies will help us predict how signaling networks in human cells will respond to stimuli; how they can be modified or rebuilt to generate a desired cellular output; and how they can be modulated for therapeutic purposes.