ABSTRACT Adrenergic (ADRN) neuroblastoma cells have a paradoxical increase in TET1 expression and 5‐hydroxymethylcytosine (5‐hmC) deposition in hypoxia. However, the effect of hypoxia on the mesenchymal (MES) lineage remains less well understood. To identify lineage specific hypoxia responses, we evaluated 5‐hmC and RNA expression in a panel of ADRN and MES cells cultured in normoxic or hypoxic conditions. In hypoxia, MES cells had only a modestly elevated expression of hypoxia signaling and no phenotypic changes. In contrast, ADRN cells showed increased 5‐hmC deposition and decreased mitochondrial function in hypoxia. In hypoxia, only ADRN cells had increased expression of MES signature genes ( p < 0.05) and related pathways including TNF‐α signaling. Publicly available RNA‐Seq data of diagnostic tumors was accessed (GSE62564 and GSE73517). Each tumor was assigned a hypoxia score using a published hypoxia signature. A MES/hypoxia signature comprising 94 MES signature genes that had increased expression in ADRN cells exposed to hypoxia was also generated. This MES/hypoxia signature was significantly correlated with a T cell infiltration signature ( r = 0.66, p = 2.3 × 10 −12 ). Kaplan–Meier analysis and the log rank test assessed overall survival (OS) differences between groups. High‐risk patients with hypoxic tumors that had high MES/hypoxia scores had significantly improved 3‐year OS compared to those with low MES/hypoxia scores (71% vs. 40%; p = 0.0054). Superior survival was also observed in high‐risk patients with hypoxic tumors that had high MES/hypoxia scores in the validation cohort (GSE73517; n = 28; 3‐year OS 78% vs. 26%, p = 0.0012). Our results suggest that hypoxia changes expression of genes in ADRN cells towards MES cells.
Chaves et al. (Sun,) studied this question.