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Challenging the gaps in global cancer concepts by a real life tumor: human childhood neuroblastoma

Final Report Summary - REALLIFECANCER (Challenging the gaps in global cancer concepts by a real life tumor: human childhood neuroblastoma)

Many tumour types respond to therapy by complete clinical remission, but nevertheless relapse in subsequent years as therapy resistant lethal disease. This pattern is also followed by high stage neuroblastoma, a childhood tumour of the peripheral adrenergic nervous system. A major question is therefore why and how tumours relapse as resistant disease. Two hypotheses prevail. The clonal evolution model proposes that tumours continuously accumulate gene mutations and treatment selects for mutations conferring resistance. The phenotypic plasticity model is based on the observation that several tumour types appear to include two phenotypically divergent tumour cell types. Besides well-defined tumour cells with markers of the tissue of origin, also immature tumour cells can be detected which are often more drug resistant. We investigated both genetic and phenotypic intra-tumour heterogeneity in neuroblastoma.
Elaborate mutation analyses of large neuroblastoma series including relapses revealed that neuroblastoma have only few gene mutations and a relation between specific mutations and drug resistance was not evident. In contrast, most neuroblastoma tumours were found to include tumour cells with two specific phenotypes. ADRN-type cells showed adrenergic lineage markers and MES-type cells were immature and lacked such markers. MES and ADRN cells have strongly divergent gene expression patterns and differ in epigenetic up-make of their genomes. Nevertheless, they can spontaneously transdifferentiate into one another. We identified for both cell types a set of 20 transcription factors that control each of the cell types and their epigenetic marks. The MES and ADRN phenotypes appeared to correspond faithfully with two stages of the normal embryonal development of the peripheral adrenergic system. Intra-tumour heterogeneity thus mimics normal development.
The immature MES-type cells appeared to be resistant to most clinically used drugs, including chemotherapy, retinoic acid and ALK-inhibitors. ADRN-type cells are killed by these drugs, but MES cells may escape therapy and seed relapses. Retinoic acid and ALK-resistance resulted from differences between MES and ADRN cells in specific molecular signalling routes. The same differences were found between the two normal developmental stages that are mimicked by MES and ADRN cells. Intra-tumour heterogeneity in neuroblastoma therefore reflects normal developmental stages including signalling pathways that define sensitivity or resistance to therapy.
These findings imply that combination therapy with drugs that kill ADRN as well as MES-type cells may abate relapse development. We identified drugs specific for each cell type and combination therapy in neuroblastoma tumours transplanted in mice were encouraging and urge to continue these investigations.