Abstract A055 YAP/TAZ induce a noradrenergic to mesenchymal transition through a core regulatory circuitry including FOSL2, TEAD4 and RUNX1 promoting invasion and chemoresistance in neuroblastoma

Abstract INTRODUCTION - Intra-tumoral heterogeneity and plasticity have recently emerged from in vitro analyses of neuroblastoma cell lines, pointing the coexistence and the ability of certain tumor cells to switch from a noradrenergic identity towards a phenotype with mesenchymal properties, defining a “Noradrenergic to Mesenchymal Transition”. In vitro, mesenchymal tumor cells are more resistant to treatments currently used in the clinic and have higher invasion properties. While the noradrenergic identity is well characterized at the molecular level, the intrinsic and extrinsic factors controlling the mesenchymal phenotype and transition states remain to be determined. METHODS - Using several cellular models, we explored the transition states between the noradrenergic and mesenchymal identities by single-cell RNAseq experiments. Pharmacological and genetic tools (siRNAs, shRNAs, CRISPR KO, overexpression) along with functional experiments (ChIPseq, RNAseq, cell proliferation and invasion assays) were used to investigate the role of several factors in the acquisition and maintenance of mesenchymal properties. RESULTS - Epigenomic and transcriptomic data demonstrated the expression of two co-transcriptional regulators YAP and TAZ (WWTR1), along with known target genes of a pan-cancer signature, specifically in mesenchymal neuroblastoma cells. We then characterized YAP/TAZ DNA binding sites in mesenchymal cells, showing a specific association to super-enhancers and unveiled a core regulatory circuitry involving FOSL2, TEAD4 and RUNX1 transcription factors. YAP/TAZ inhibition approaches highlighted their role in mesenchymal cell proliferation. Our data further indicated that YAP/TAZ and their target genes are expressed during the noradrenergic to mesenchymal transition in vitro and conversely repressed during the reverse transition in vivo. Strikingly, YAP/TAZ overexpression in noradrenergic cells induced a full transition towards a mesenchymal state with a transcriptional reprogramming and the acquisition of invasion and chemoresistance properties. Finally, down-regulation of YAP/TAZ expression in our plasticity models was enough to abrogate the noradrenergic to mesenchymal transition. CONCLUSION - While YAP/TAZ have been associated with several hallmarks of cancers, their role in neuroblastoma was still unknown. In this work, we uncover the specific role of YAP/TAZ as master regulators of the mesenchymal identity and key actors of the noradrenergic to mesenchymal reprogramming in neuroblastoma. Understanding the molecular mechanisms controlling cellular plasticity is a crucial step to propose new therapeutic strategies for patients with high-risk disease. Citation Format: Margot Gautier, Amira Kramdi, Caroline Louis-Brennetot, Cécile Pierre-Eugene, Camille Lossec, Olivier Delattre, Cécile Thirant, Isabelle Janoueix-Lerosey. YAP/TAZ induce a noradrenergic to mesenchymal transition through a core regulatory circuitry including FOSL2, TEAD4 and RUNX1 promoting invasion and chemoresistance in neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A0.