Abstract 1470: ASCL1 dimerizes with TCF12 protein and activates BMP-SMAD1 pathway during subtype switching from mesenchymal towards adrenergic neuroblastoma

Abstract

Abstract Recently, several studies have demonstrated two semi-stable and interchangeable subtypes of neuroblastoma, namely mesenchymal (MES) and adrenergic (ADRN) subtypes, which are associated with the early neural crest and committed adrenergic neural progenitor stages, respectively. Each of these subtypes is controlled by a different set of transcription factors forming the core regulatory circuit (CRC) and exhibits different enhancer and transcription profiles. However, transcription factors that drives transition of the subtype switching and the corresponding regulated signaling pathways remain to be investigated. In this study, we demonstrate that ASCL1, a critical member of the ADRN CRC, can induce a subtype switching from MES to ADRN neuroblastoma. Our study shows that a forced expression of ASCL1 in MES neuroblastoma cells results in cell cycle arrest and cell differentiation towards the ADRN lineage with induction of ADRN gene expression, such as DLL3 and DBH. Furthermore, we have identified TCF12 as an important interaction partner of ASCL1 via SILAC analysis. ASCL1 forms a complex with TCF12 and regulates the expression of downstream target genes. On the other hand, overexpression of ASCL1 inhibits existing MES specific TGFβ-SMAD2/3 signaling pathway, while it activates BMP-SMAD1 signaling pathway. Interestingly, activation of BMP-SMAD1 signaling pathway results in the upregulation of the ID proteins, which can form dimer with TCF12 protein and sequester it away from ASCL1 protein. Thus, the BMP SMAD1-ID protein signaling cascade in turn serves as a negative feedback loop to prevent the cells from terminal differentiation via equilibration of the amount of ASCL1-TCF12 dimer. In summary, ASCL1 can induce the subtype switching and partially define the ADRN transcription program. ASCL1 serves as a lineage master initiator that characterizes ADRN neuroblastoma. Citation Format: Lu Wang, Tze King Tan, Hyoju Kim, Dennis Kappei, Shi Hao Tan, A. Thomas Look, Takaomi Sanda. ASCL1 dimerizes with TCF12 protein and activates BMP-SMAD1 pathway during subtype switching from mesenchymal towards adrenergic neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1470.