Neuroblastoma Tumor Microenvironment: tumor growth and immune regulation

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

As an update to Specific Aim 1 of this project, we utilized 2/6 Patient Derived Xenografts(PDX) that were developed in 2024, to develop in vitro organoids cultures to study Neuroblastoma tumor cell heterogeneity and how environmental stimulii activate signaling paths that control gene programs associated with tumor formation or growth arrest and differentiation. By using technologies like chromosomal paint we have been able to document different Neuroblastoma tumor cell types carrying amplification of the oncogene MYCN evolve during in vitro culture to carry the amplification either within chromosomes or as extrachromosomal circular DNAs, while some cells lose the amplified MYCN genes. We have noted different transcriptomes and biologic properties evolve with these differences in the cellular location of the MYCN amplification as well as changes in MYCN amplification copy number. Studies are underway to examine cellular responses to treatment with cytotoxic drugs used to treat patients with Neurobastoma tumors to assess how therapies alter tumor evolution. In Specific Aim 2 we have identified that the SWI/SNF nucleosome remodeling complex is important in regulating cancer evolution and there is a significant block in the development of a Neuroblastoma cell type with characteristics of neural crest mesenchymal like cells. Neural crest like mesenchymal neuroblastoma tumor cells are resistant to cytotoxic drugs. We have identified that a degrader of SMARCA2/4 which is the catalytic subunit of the SWI/SNF remodeling complex can inhibit the the formation of the drug resistant neural crest-like mesenchymal NB tumor cells. We are currently evaluating a small molecule inhibitor of SMARCA2/4 that is in clinical trials to test its efficacy in blocking drug resistant NB tumor cells. The key finding in this study was the molecular mechanism by which the pretreatment of the NB spheroids with the SMARCA2/4 degrader prevented the expression of the drug resistant mesenchymal transcriptional program and thus cells retained sensitivity to cytotoxic drug. Thus the combined treatment with the inhibitor of the SMARCA2/4 ATPase and standard chemotherapy prevented the development of drug resistant NB cells.