Abstract 1718: The lysine demethylase KDM2A regulates tumor cell clustering to potentiate metastasis

Abstract Approximately 70% of patients diagnosed with non-small cell lung cancer (NSCLC) are not eligible for curative resection, often due to disseminated disease at diagnosis. Thus, the advent of novel therapeutics, especially those efficacious for metastatic disease, is of primary importance. Metastasis correlates with epigenetic alterations that drive tumor plasticity and adaptive heterogeneity in response to the multiple microenvironments metastatic cells see, yet the molecular mechanisms underlying these epigenetic alterations remain poorly understood. We performed a functional genomic screen and identified the lysine 36 on histone H3 (H3K36) demethylase KDM2A as a mediator of in vivo and in vitro metastatic competence in multiple models of NSCLC. KDM2A depletion in highly metastatic NSCLC cell lines reduces their capacity to form multi-tumor cell clusters. In vivo, KDM2A depletion does not impact lung orthotopic tumor cell growth or the total number of circulating tumor cells (CTCs) but does reduce their ability to colonize distant metastatic sites. This is consistent with the fact that human CTCs found in clusters are more metastatic than CTCs which disseminate as single-cells. Because the molecular and biological consequences of H3K36 regulation are context dependent, we performed for the first time an integrated transcriptomic-epigenomic analysis of target gene regulation, KDM2A genomic binding, H3K36 methylation, and H3K27 acetylation, in metastatic cell clusters. KDM2A enhances the expression of cell adhesion and anti-oxidant genes, while suppressing inflammatory gene responses, and this regulation preferentially occurs in tumor cell clusters. Transcriptomic analysis of CTCs from patients confirms that KDM2A regulated transcriptional responses correlate with metastatic relapse across multiple cancer types. Moreover, KDM2A may function both as a transcriptional activator and repressor in metastatic clusters. As KDM2A encodes for several domains which can independently regulate E3-ubiqutin ligation, H3K36me2 demethylation, and DNA methylation, we have also performed a structure function analysis of K2MDA in the context of metastatic phenotypes. Thus, the distinct biochemical functions of KDM2A in relation to its regulation of CTC gene transcription and histone modification will also be presented. In conclusion, we have identified KDM2A as a novel regulator of NSCLC metastatic spread. The ability to inhibit KDM2A with small molecule inhibitors may be translated into effective therapeutic interventions for NSCLC patients with metastasis disease. Citation Format: Carolyn Kravitz, Kiran D. Patel, Wesley L. Cai, Anna Arnal-Estapé, Dejian Zhao, Emily Wingrove, Laura Stevens, Thomas F. Westbrook, Qin Yan, Don X. Nguyen. The lysine demethylase KDM2A regulates tumor cell clustering to potentiate metastasis [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 1718.