Abstract PO-111: Identifying epigenetic mechanisms for proliferation and self-renewal of tumor-propagating cells (TPC) in lung cancer

Abstract

Abstract Lung cancer is a leading cause of death worldwide and lung adenocarcinoma (LUAD) is the most common subtype. LUAD tumors have a functional heterogeneity in regard to tumor-propagating capacity. Cells with an increased capacity to sustain tumor growth are called tumor-propagating cells (TPC or cancer stem cells) and they have been associated with chemoresistance and tumor relapse. A TPC population identified in a mouse model of LUAD (Kras G12D/wt/p53 fl/fl)(KP) sustain growth in serial orthotopic transplantations and are distinguished by expression of Notch receptors. Furthermore, TPCs gene expression signature is associated with a worse prognosis in human cancer. My hypothesis is the TPCs gene expression may be regulated by global chromatin alterations driven by epigenetic regulators. In LUAD, secondary tumors derived from TPC or non-TPC sorted populations regenerated both TPC and non-TPC populations, recapitulating the heterogeneity of the original tumor, suggesting TPC plasticity and supporting an epigenetic regulation. The main goal of my work is to identify and understand epigenetic mechanisms of TPC maintenance in LUAD and determine their relevance for other cancers. TPC and non-TPC populations show dramatic differential protein expression of H3K4me3 and H4K16ac histone modifications associated with transcription activation. To better understand how these histone marks alter the genome of TPCs, I performed ATAC-seq (Assay for Transposase-Accessible Chromatin followed by sequencing) and CARM (CRISPR/Cas9-assisted removal of mitochondrial DNA) to remove mitochondrial DNA prior to sequencing in both TPC and non-TPC populations from primary cells of KP mouse models. I have identified unique open chromatin regions in TPCs which were associated to the closest gene. For TPCs, the main enriched cluster of pathways included Notch signaling pathway and pathways associated with remodeling of the tumor microenvironment. In parallel, I am customizing an epigenetic short hairpin RNA (shRNA) library to screen epigenetic regulators implicated in plasticity and self-renewal ability of TPCs and I will evaluate them whether function through Notch signaling. Citation Format: Eunice Lopez Fuentes, Alejandro Sweet-Cordero. Identifying epigenetic mechanisms for proliferation and self-renewal of tumor-propagating cells (TPC) in lung cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-111.