Abstract C106: Identification of nucleic acid drug candidates against mesenchymal transition and its application to breast cancer and glioblastoma cells

Abstract

Abstract Cancer stem-like cells (CSLC) have a feature of epithelial-mesenchymal transition (EMT) responsible for tumor heterogeneity and therapeutic resistance. To identify molecular targets of CSLC, we underwent shRNA screening for epithelialization of MDA-MB-231 mesenchymal breast cancer cell line with novel EMT/MET dual reporter system and identified 2 shRNAs (shP1 and shH1) which reverse EMT in mesenchymal breast cancer as well as glioblastoma cells. While mesenchymal breast cancer cells undergo adipogenic differentiation upon PPAR gamma activation, shP1-induced epithelialization suppresses adipogenic differentiation. Of the two shRNAs, the shH1 strongly inhibited their growth, indicating shH1-specific sequence has a therapeutic potential for nucleic acid therapeutics. Metabolome/transcriptome analyses of immortalized human mammary epithelial cells (HMLE) undergoing EMT in the presence of absence of H-Ras oncogene revealed global metabolic change upon EMT, including reduced glycolysis, increased shunting to pentose phosphate pathways, shift in TCA, and increased glutathione biosynthesis. Ras-mesenchymal CSLC cells overcame the effects of EMT on glycolysis and acquired hybrid metabolic state. In summary, we have revelaed metabolic plasticity of mesenchymal cancer cells and identified nucleic acid drug candidates against mesenchymal transition. Citation Format: Kiyotsugu Yoshikawa, Rei Takahashi. Identification of nucleic acid drug candidates against mesenchymal transition and its application to breast cancer and glioblastoma cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C106.