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Figure 2. A: Cartoon showing the models of NB-CSCs-associated tumor resistance and tumor relapse. Pre-existing NB-CSCs survive IMCT and undergo self-renewal, clonal expansion and development of non-stem tumor cells, resulting in tumor relapse. In parallel, the non-stem tumor cells that survive IMCT under unique circumstances undergo extensive genetic and molecular rearrangements that lead to their transformation into induced CSCs (iCSCs). Generation of iCSCs with unique stem-cell characteristics of self-renewal and expansion results in tumor maintenance and relapse. B: Schematic representation of the molecular characteristics of NB-CSCs (pre-existing NB-CSCs and induced iCSCs) and their signaling flow-through that dictates therapy resistance and NB disease evolution. IMCT: intensive multi-modal clinical therapy; NB: neuroblastoma; CSCs: cancer stem cells; iCSCs: induced cancer stem cells; N-Type: neuroblastic type cells; I-Type: intermediate type neuroblastoma cells; S-Type: Schwann-type cells