Exposing hidden targets of drug resistance in cancer by mapping the epitranscriptome at single-cell resolution

Introduction

Drug resistance is one of the biggest challenges in the clinical management of breast cancer (BC), but the underlying mechanisms are still not fully understood. What we do know is that epigenetic mechanisms play a key role in the adaptation of cancer cells to therapy, which is why they have become a prime field of investigation.

Current Understanding

Single-cell profiling of epigenetic DNA and histone modifications have already revealed intriguing and actionable insights into tumor heterogeneity. For the most recently discovered epigenetic layer, however, which consists of RNA modifications, we have not yet reached single-cell resolution.

Epitranscriptomics

The exciting potential of RNA modifications to fine-tune the processing and expression of mRNAs is currently an area of intense research termed ‘Epitranscriptomics’. The most prevalent and best-studied of these mRNA modifications, N6-methyladenosine (m6A), has recently been linked to drug resistance in cancer.

Research Findings

Our lab has uncovered a new m6A-based layer of dysregulation of a major cancer pathway driving therapy resistance in BC. The ability to study m6A in single cells holds great promise as it would enable us to further delineate tumor heterogeneity and to find novel drug resistance targets that have eluded us so far.

Proposed Aims

I propose to:

1. Develop a method for streamlined m6A mapping at single-cell resolution (Aim 1).
2. Apply it to triple-negative BC (TNBC) cells driven to chemoresistance in cell culture, mice, and human samples to determine uncharted targets of drug resistance (Aim 2).
3. Disrupt m6A-regulated chemoresistance targets in order to prevent therapy failure (Aim 3).

Alignment with Skills

These aims are aligned with my knowledge and skills related to both m6A and drug resistance. This unique and comprehensive analysis of the single-cell m6A methylome will provide invaluable new insights into the unknown epigenetic characteristics of chemoresistance and will pave the way for new therapeutic interventions.