Genomic dissection of cellular plasticity and transcriptional memory in drug tolerance.

Non-genetic cellular heterogeneity has a poorly understood origin but a significant impact on human health.

A clear example is the phenotypic switch associated with the appearance of drug-tolerant persister cells that can escape anticancer treatment and provide a reservoir from which resistant clones may evolve. There is an urgent need to develop therapies targeting these processes, however they are not yet fully understood.

Here, we propose to investigate the fundamental gene expression mechanism controlling cellular plasticity.

We will investigate the factors allowing cells previously exposed to a drug to be more resistant to a second exposure, with a focus on transcriptional memory.

We will investigate which factors facilitate the transition between sensitive and tolerant phenotypic estates in absence of drug treatment. We will develop a novel single-cell RNA-Seq approach able to record a snapshot of the ancestral transcriptome.

This will allow us to link past and present phenotypes, and facilitate the identification of events preceding the phenotypic switches that would be ideal therapeutic targets. Finally, we will integrate and validate all results using in vitro and in vivo systems.

In summary, this project promises to improve our mechanistic understanding of the regulation of phenotypic switches in cancer and aims to identify new therapeutic targets that could increase the efficacy of current treatments.