Single cell RNA-seq shows cellular heterogeneity and lineage expansion in a mouse model of SHH-driven medulloblastoma support resistance to SHH inhibitor therapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129730 | GEO | 2019/04/13
REPOSITORIES: GEO
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Project description:Targeting oncogenic pathways holds promise for brain tumor treatment, but inhibition of Sonic Hedgehog (SHH) signaling has failed in SHH-driven medulloblastoma. Cellular diversity within tumors and reduced lineage commitment can undermine targeted therapy by increasing the probability of treatment-resistant populations. Using single-cell RNA-seq and lineage tracing, we analyzed cellular diversity in medulloblastomas in transgenic, medulloblastoma-prone mice, and responses to the SHH-pathway inhibitor vismodegib. In untreated tumors, we find expected stromal cells and tumor-derived cells showing either a spectrum of neural progenitor-differentiation states or glial and stem cell markers. Vismodegib reduces the proliferative population and increases differentiation. However, specific cell types in vismodegib-treated tumors remain proliferative, showing either persistent SHH-pathway activation or stem cell characteristics. Our data show that even in tumors with a single pathway-activating mutation, diverse mechanisms drive tumor growth. This diversity confers early resistance to targeted inhibitor therapy, demonstrating the need to target multiple pathways simultaneously.
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Project description:Medulloblastoma is the most common pediatric CNS cancer. In order to identify important molecules important for deregulated tumor cell growth, we use microarray to detail the global gene expression profile in Shh-driven mouse medulloblastomas and determine the most differentially expressed genes compared to the control wild-type cerebellum.
2012-03-15 | GSE36525 | GEO
Project description:Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using iPS cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carrying a germline mutation in the Sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Re-transplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, enhanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model we identified LGALS1 to be a GLI target gene that is upregulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we demonstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression, and to identify novel putative targets.
2020-07-16 | GSE106718 | GEO
Project description:Medulloblastoma is the most common pediatric CNS cancer. In order to identify important molecules important for deregulated tumor cell growth, we use microarray to detail the global gene expression profile in Shh-driven mouse medulloblastomas and determine the most differentially expressed genes compared to the control wild-type cerebellum. Medulloblastoma and control cerebellum tissues were dissected and processed for RNA extraction and microarray analyses using Affymetrix Mouse Gene 1.0 ST. The mice were from a mixed genetic background involving C57BL/6 and C3H strains.
2012-03-15 | E-GEOD-36525 | biostudies-arrayexpress
Project description:Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies.
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Project description:Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
| S-EPMC7979819 | biostudies-literature
Project description:Background: Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Metastasis and relapse are the leading causes of death in MB patients. The initiation of the SHH subgroup of MB (SHH-MB) is due to the aberrant activation of Sonic Hedgehog (Shh) signaling. However, the mechanisms for its metastasis are still unknown. Results: AMP-dependent protein kinase (AMPK) restrains the activation of Shh signaling pathway, thereby impeding the proliferation of SHH-MB cells. More importantly, AMPK also hinders the growth and metastasis of SHH-MB cells by regulating NF-kB signaling pathway. Furthermore, Vismodegib and TPCA-1, which block the Shh and NF-kB pathways, respectively, synergistically restrained the growth, migration, and invasion of SHH-MB cells. Conclusions: This work demonstrates that AMPK functions through two signaling pathways, SHH-GLI1 and NF-kB. AMPK-NF-kB axis is a potential target for molecular therapy of SHH-MB, and the combinational blockade of NF-kB and Shh pathways confers synergy for SHH-MB therapy.
2023-07-01 | GSE218076 | GEO
Project description:Medulloblastoma is heterogeneous, being characterized by molecular subgroups that demonstrate distinct gene expression profiles. Activation of the WNT or SHH signaling pathway characterizes two of these molecular subgroups, the former associated with low-risk disease and the latter potentially targeted by novel SHH pathway inhibitors. This manuscript reports the validation of a novel diagnostic immunohistochemical method to distinguish SHH, WNT, and non-SHH/WNT tumors and details their associations with clinical, pathological and cytogenetic variables. A cohort (n = 235) of medulloblastomas from patients aged 0.4-52 years was studied for expression of four immunohistochemical markers: GAB1, β-catenin, filamin A, and YAP1. Immunoreactivity (IR) for GAB1 characterizes only SHH tumors and nuclear IR for β-catenin only WNT tumors. IRs for filamin A and YAP1 identify SHH and WNT tumors. SHH, WNT, and non-SHH/WNT tumors contributed 31, 14, and 55% to the series. All desmoplastic/nodular (D/N) medulloblastomas were SHH tumors, while most WNT tumors (94%) had a classic phenotype. Monosomy 6 was strongly associated with WNT tumors, while PTCH1 loss occurred almost exclusively among SHH tumors. MYC or MYCN amplification and chromosome 17 imbalance occurred predominantly among non-SHH/WNT tumors. Among patients aged 3-16 years and entered onto the SIOP PNET3 trial, outcome was significantly better for children with WNT tumors, when compared to SHH or non-SHH/WNT tumors, which showed similar survival curves. However, high-risk factors (M+ disease, LC/A pathology, MYC amplification) significantly influenced survival in both SHH and non-SHH/WNT groups. We describe a robust method for detecting SHH, WNT, and non-SHH/WNT molecular subgroups in formalin-fixed medulloblastoma samples. In corroborating other studies that indicate the value of combining clinical, pathological, and molecular variables in therapeutic stratification schemes for medulloblastoma, we also provide the first outcome data based on a clinical trial cohort and novel data on how molecular subgroups are distributed across the range of disease.
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Project description:Using 10xGenomics single cell RNAseq library creation and Illumina sequencing, we generated single cell RNAseq data for 12 samples of myeloid cells in mouse sonic hedgehog medulloblastomas to characterize their heterogeneity in comparison to control peripheral myeloids cells and homeostatic cerebellar myeloid cells from young mice without significant tumors. We then sequenced myeloid cells in tumors that were treated with two modalities, sonic hedgehog inhibition and radiation, to determine the differential recruitment of myeloid cells. Finally we sequenced samples of myeloid cells from irradiated Ccr2 knockout mice to further determine the change in recruitment of myeloid cells and their heterogeneity when monocyte-derived macrophages are reduced.
2021-02-13 | GSE166691 | GEO
Project description:We report scRNA-seq data showing the effect of Prkaa1/2 deletion on medulloblastomas that form in Smo-mutant mice. We generate tumor-bearing mice by breeding hGFAP-Cre/Prkaa1fl/fl/Prk112fl/fl and Prkaa1fl/fl/Prk112fl/fl/SmoM2 mouse lines to prodce tumor-prone progeny with homozygous, conditional deletion of Prkaa1 and Prkaa2 (G-SmoAMPK mice). We compared tumors from G-Smo mice withintact Prkaa1 and Prkaa2 to tumors from G-SmoAMPK mice, using Drop-seq-based scRNA-seq.
2021-12-08 | GSE190297 | GEO