Abstract PO-112: miR-149-3p inhibits the glioma stem cell phenotype and re-sensitizes therapy-resistant GBM cells

Abstract

Abstract Intra-tumor heterogeneity presents one of the biggest challenges in the development of solid cancer therapeutics. Cells within the same tumor display distinct phenotypes that affect their growth rate, survival, migration, therapy-response, and tumor-propagating capacity. We now understand cancer stem cells (CSCs) play critical roles in driving intra-tumor cellular heterogeneity by establishing dynamic cellular transitions within tumors. GBM are highly aggressive tumors that display a poorly differentiated cell phenotype characterized by high expression of genes enriched in embryonic stem cells (ESCs). Lineage-tracing experiments show that stem-like cells are responsible for GBM re-growth after therapy and this process is in part mediated by known drivers of stemness (e.g. Sox2). There is a strong correlation between the expression of stem cell drivers and markers and tumor recurrence in multiple cancers, including GBM. We and others have established that reprogramming transcription factors Oct4 and Sox2 are important drivers of the stem-cell, tumor and therapy-resistant phenotype in GBM. We present data showing that GBM cells expressing transgenic Oct4 and Sox2 are more resistant to ionizing radiation (IR) treatment and exposing GBM neurospheres to temozolomide (TMZ) and IR gives rise to a cell sub-set with higher gene expression levels of Oct4 and Sox2 compared to untreated cells. The clinical and potential therapeutic relevance of this phenotype is supported by multi-dimensional transcriptome analyses that identifies a group of genes induced by Oct4 and Sox2 enriched in recurrent GBM. The promiscuous quality of miRNAs is an underexploited characteristic that could allow the targeting of multiple parallel oncogenic pathways using a single agent, enhancing therapeutic efficacy and reducing chances of tumor recurrence. To explore this untapped potential, we predicted miRNAs likely to target the transcripts induced by Oct4/Sox2 in recurrent GBM and identified miR-149-3p as a high-priority candidate. Importantly, transient expression of miR-149-3p simultaneously repressed these transcripts in GSCs as measured by qRT-PCR, concurrent with a decrease in the capacity of both parental and GSCs expressing transgenic Oct4/Sox2 to self-renew as spheres, a biomarker of cell stemness and tumor-propagating potential. Additionally, transient expression of miR-149-3p also re-sensitized therapy-resistant GBM neurospheres to TMZ treatment. These results show this resistant phenotype is reversible and support our hypothesis that GSC-driving mechanisms induce a subset of genes that give rise to therapy-resistant GBM cells and suggests that miR-149-3p can be developed as a therapeutic for recurrent GBM. Citation Format: Hernando Lopez-Bertoni. miR-149-3p inhibits the glioma stem cell phenotype and re-sensitizes therapy-resistant GBM cells [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-112.