Abstract 4347: Cell-type specific transcriptional regulation of APOBEC3A in cancers

Abstract

Abstract APOBEC3s (A-H) are a family of seven cytosine deaminases that inactivate viruses as part of the innate immune response. However, APOBEC3A and APOBEC3B have been found to mediate mutagenesis in tumor genomes by deaminating ssDNA that transiently arise during transcription and DNA replication. The mechanisms that trigger these enzymes to generate high mutation burdens in some cancers and affect disease progression and clinical outcomes are largely unknown. Here, we explored cell-type-specific transcriptional regulation of APOBEC3s using single-nucleus/cell RNA-seq (sn/scRNA-seq) data (>100 samples and >300,000 cells) from four tumor types - bladder, lung, breast, and kidney - that display different levels of APOBEC-induced mutation burden. Our analyses revealed that among seven members of the APOBEC3 family, APOBEC3A is expressed in a cell-type-specific manner. The expression was predominant in KRT13 and CDH12 epithelial cell-types and inflamed macrophages. The APOBEC3A+ epithelial cell populations were abundant in the bladder, moderate in the lung and breast, and nearly absent in the kidney tumors. APOBEC3A expression correlated with interferon and pro-inflammatory signaling in KRT13+ cells. Transcription factors ELF3 and ATF3 were significantly upregulated in APOBEC3A+ KRT13 cells. Pseudotime analysis of sn/scRNA-seq data revealed that APOBEC3A cells are in epithelial-mesenchymal transition. Finally, several gene markers defining APOBEC3A+ KRT13 cell types were identified. Ongoing analyses include investigations into clinical correlates, cell-type-specific mutation burdens, and validation through in vitro functional approaches. Our results propose that APOBEC3A is turned on in specific epithelial cell types by multiple signaling pathways during tumorigenesis, thereby driving tumor heterogeneity, particularly in high mutation-burden cancers. Citation Format: Dhanusha Yesudhas, Bilal Lone, Kelly Butler, Arup Chakraborty, Abdul Rouf Banday. Cell-type specific transcriptional regulation of APOBEC3A in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4347.