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Macrophage-Tumor Cell Interaction Promotes ATRT Progression and Chemoresistance (NODSCID)

ABSTRACT: Atypical teratoid/rhabdoid tumors (ATRT) are known for their heterogeneity concerning pathophysiology and outcome. However, predictive factors within distinct subgroups still need to be uncovered. Using multiplex immunofluorescent staining and singe-cell RNA sequencing we unraveled distinct compositions of the immunological tumor microenvironment (TME) across ATRT subgroups. CD68+ cells predominantly infiltrate ATRT-SHH and ATRT-MYC and are a negative prognostic factor for patients’ survival. Within the murine ATRT-MYC and ATRT-SHH TME, Cd68+ macrophages are core to intercellular communication with tumor cells. In ATRT-MYC distinct tumor cell phenotypes express macrophage marker genes. These cells are involved in the acquisition of chemotherapy resistance in our relapse xenograft mouse model. In conclusion, the tumor cell-macrophage interaction contributes to ATRT-MYC heterogeneity and tumor recurrence.

ORGANISM(S): Mus musculus

PROVIDER: GSE141533 | GEO | 2020/05/14

REPOSITORIES: GEO

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Macrophage-Tumor Cell Interaction Promotes ATRT Progression and Chemoresistance (GEMM)

Project description:Atypical teratoid/rhabdoid tumors (ATRT) are known for their heterogeneity concerning pathophysiology and outcome. However, predictive factors within distinct subgroups still need to be uncovered. Using multiplex immunofluorescent staining and singe-cell RNA sequencing we unraveled distinct compositions of the immunological tumor microenvironment (TME) across ATRT subgroups. CD68+ cells predominantly infiltrate ATRT-SHH and ATRT-MYC and are a negative prognostic factor for patients’ survival. Within the murine ATRT-MYC and ATRT-SHH TME, Cd68+ macrophages are core to intercellular communication with tumor cells. In ATRT-MYC distinct tumor cell phenotypes express macrophage marker genes. These cells are involved in the acquisition of chemotherapy resistance in our relapse xenograft mouse model. In conclusion, the tumor cell-macrophage interaction contributes to ATRT-MYC heterogeneity and tumor recurrence.

2020-05-14 | GSE141532 | GEO

Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups [DNAmeth_EPICarray]

Project description:Atypical teratoid rhabdoid tumors (ATRT) are divided into MYC, TYR and SHH subgroups, suggesting diverse lineages of origin. Here, we investigate the imaging of human ATRT at diagnosisand the precise anatomic origin of brain tumors in the Rosa26; Cre-ERT2::Smarcb1flox/flox model. This cross-species analysis points to an extra-cerebral origin for MYC tumors. Additionally, we clearly distinguish SHH ATRT emerging from the cerebellar anterior lobe (CAL) from those emerging from the basal ganglia (BG) and intra-ventricular (IV) regions. Molecular characteristics point to the midbrain-hindbrain boundary as the origin of CAL SHH ATRT, and to the ganglionic eminence as the origin of BG/IV SHH ATRT. Single-cell RNA sequencing on SHH ATRT supports these hypotheses. Trajectory analyses suggest that SMARCB1 loss induces a de-differentiation process mediated by repressors of the neuronal program such as REST, ID and the NOTCH pathway.

2023-09-20 | GSE242089 | GEO

Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups [bulkRNAseq_primaryATRT]

2023-09-20 | GSE241831 | GEO

Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups [scRNAseq_ATRT_CAL]

2023-09-20 | GSE241737 | GEO

Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups [scRNAseq_mouseRT_R26SHH]

2023-09-20 | GSE241736 | GEO

Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups [bulkRNAseq_mouseRT_R26]

2023-09-20 | GSE241734 | GEO

Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups [bulkRNAseq_ATRT_cellLines]

2023-09-20 | GSE241733 | GEO

Gene expression data from ATRT tumor samples

Project description:Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large series of human ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets. 49 ATRT samples were selected for RNA extraction and hybridization on Affymetrix Affymetrix Human Genome U133 Plus 2.0 Arrays. ---------------------------------------- This submission consists of the expression data for 49 of 170 samples only

2016-03-02 | E-GEOD-70678 | biostudies-arrayexpress

Gene expression data from ATRT tumor samples

2016-03-02 | GSE70678 | GEO

Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities WGS

Project description:Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically uniquely defined by alterations in the SWI/SNF chromatin remodeling complex membersÃ‚Â SMARCB1Ã‚Â orÃ‚Â SMARCA4. ATRTs can be further classified in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinicalÃ‚Â in vitroÃ‚Â models representative of the different molecular subgroups.Ã‚Â Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT-MYC and ATRT-SHH subgroups. Whereas ATRT-MYC universally displayed high sensitivity to multi-targeted tyrosine kinase inhibitors, ATRT-SHH showed a more heterogeneous response with a subset showing high sensitivity to Notch inhibitors, which corresponded to high expression of Notch receptors. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing a representative pre-clinical model which enables the development of subgroup-specific therapies.

| EGAS00001006865 | EGA

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