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Neuroblastoma, a type of cancer that is common in children, is composed of two genetically clonal but epigenetically distinct cell types: mesenchymal (MES) and adrenergic (ADRN) types, controlled by super‐enhancer‐associated lineage‐specific transcription factor networks. Mesenchymal‐type cells are more migratory, resistant to chemotherapy, and prevalent in relapse tumors. Importantly, both cell types spontaneously transdifferentiate into one another, and this interconversion can be induced by genetic manipulations. However, the mechanisms of their spontaneous transdifferentiation and extracellular factors inducing this phenomenon have not yet been elucidated. Using a unique approach involving gene set enrichment analysis, we selected six ADRN and 10 MES candidate factors, possibly inducing ADRN and MES phenotypes, respectively. Treatment with a combination of 10 MES factors clearly induced the MES gene expression profile in ADRN‐type SH‐SY5Y neuroblastoma cells. Considering the effects on gene expression profile, migration ability, and chemoresistance, a combination of tumor necrosis factor alpha (TNF‐α) and epidermal growth factor (EGF) was sufficient to synergistically induce the ADRN‐to‐MES transdifferentiation in SH‐SY5Y cells. In addition, human neuroblastoma cohort analysis revealed that the expression of  TNF  and  EGF  receptors was strongly associated with MES gene expression signatures, supporting their important roles in transdifferentiation in vivo. Collectively, we propose a mechanism of neuroblastoma transdifferentiation induced by extracellular growth factors, which can be controlled in clinical situations, providing a new therapeutic possibility.

cancer science

Combination of tumor necrosis factor‐α and epidermal growth factor induces the adrenergic‐to‐mesenchymal transdifferentiation in SH‐SY5Y neuroblastoma cells