Fig. 4: Cellular lineage evolution and multi-omic mechanisms of therapeutic resistance in neuroblastoma. | Oncogene

Fig. 4: Cellular lineage evolution and multi-omic mechanisms of therapeutic resistance in neuroblastoma.

From: Dissecting neuroblastoma heterogeneity through single-cell multi-omics: insights into development, immunity, and therapeutic resistance

Fig. 4

Schematic representation of NB cell-state transitions and resistance mechanisms under therapeutic pressure. During disease progression from diagnosis to relapse, ADR tumor cells progressively convert to MES and persister-like states, accompanied by epigenetic reprogramming and ecological remodeling. Six major resistance mechanisms are highlighted: (1) Genetic and structural drivers, MYCN ecDNA variation and clonal evolution; (2) Epigenetic and CRC remodeling, super-enhancer (SE) reorganization and PRRX1/NOTCH activation with ASCL1/PHOX2B suppression; (3) Target loss and bypass activation, receptor-ligand rewiring (e.g., HB-EGF–ERBB4) sustaining MAPK/PI3K signaling; (4) Persister and memory programs, low RNA velocity and JNK-dependent transcriptional noise reduction; (5) Immune and inflammatory vulnerability, TLR3-dsRNA activation, cGAS-STING deficiency, and GD2 plasticity; and (6) Metabolic and retinoic acid tolerance, enhanced lipid metabolism, ROS buffering, and autocrine RA synthesis. Together, these multi-layered processes drive adaptive resistance and therapeutic escape in NB.

Back to article page