Abstract 5288: Single-cell multiomics reveal divergent transcriptional and epigenetic cell states in breast cancer

Abstract

Abstract Over the recent years, single-cell sequencing studies have been used to better describe the highly heterogeneous nature of breast cancers on transcriptional and genetic levels. It is also known that breast cancers are highly driven by estrogen receptor alpha (ER), a transcription factor that’s important for mammary tissue homeostasis. However, little is known about how estrogen signaling heterogeneity affects cancer progression and response to anti-estrogen therapy at a single-cell level. Leveraging single-omic and multi-omic single-cell sequencing technologies, we tracked estrogen response in breast cancer cell and organoid models. We developed TITAN, a topic-modeling based analysis tool to reveal signaling gradients in single-cell RNA-seq data. With this approach we showed that distinct cells prioritize distinct gene groups in response to estrogen. We defined two of these gene networks to be driven by either ER or FOXM1. These same networks exist not only in all the models used in the study but also in breast cancer patient datasets. FOXM1 is activated in estrogen treated cells and the FOXM1 driven gene signature correlates with more aggressive types of disease. Our combined scRNA and scATAC-seq experiments also highlighted distinct chromatin accessibility states associated with either cell group. Using scNMT-seq in patient samples we were able to describe DNA methylation and chromatin accessibility influence on hormone signaling patterns at the single-cell level. Together, our results provide insights into defining transcriptional and epigenetic cell states in ER positive breast cancer. Citation Format: Aysegul Ors, Hisham Mohammed, Aaron R. Doe, Syber Haverlack, Mithila Handu, Ryan Mulqueen. Single-cell multiomics reveal divergent transcriptional and epigenetic cell states in breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5288.