Barcoded cell state specific transcription factors screen identifies SIX1 as a critical regulator of neuroblastoma plasticity and drug resistance

Neuroblastoma (NB) is characterized by intratumoral heterogeneity, consisting of at least two distinct cell types: adrenergic (ADRN) and mesenchymal (MES). These cell states can spontaneously interconvert, potentially driven by changes in super-enhancer landscapes and transcription factor (TF) networks. This interconversion presents a significant therapeutic challenge, as MES NB cells are less differentiated, more migratory, and drug-resistant, emerging during treatment and contributing to relapse. Therapeutic strategies targeting one state (like ADRN) may leave behind or select for more chemoresistant MES cells, complicating treatment efforts. Understanding the mechanisms behind the plasticity between the ADRN and MES states is critical for developing more effective treatments that prevent therapy resistance, tumor relapse, and improve patient outcomes. This MES cell state exhibits resistance to standard cytotoxic treatments and is associated with a more aggressive, migratory phenotype, contributing to poor therapeutic outcomes in NB. Additionally, NOTCH3 signaling drives the transition from ADRN to MES, with PRRX1 acting as a key reprogramming driver that reshapes the super-enhancer and mRNA landscapes of ADRN cells toward a MES state. However, what are the other TFs are involved with the transdifferentiation between ADRN and MES? What are the other TFs are responsible for the resistance of the cytotoxic therapies remain unclear. Furthermore, the most effective strategies to therapeutically target these pathways to prevent MES transition and overcome therapy resistance remain unknown.