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Spatial transcriptomic analysis of Sonic Hedgehog Medulloblastoma identified that loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition

ABSTRACT: Spatial transcriptomic analysis of Sonic Hedgehog Medulloblastoma identified that loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition

PROVIDER: PRJEB53588 | ENA |

REPOSITORIES: ENA

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Spatial transcriptomic analysis of Sonic Hedgehog Medulloblastoma identified that loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition

Project description:We used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of Medulloblastoma (MB) and identify how cells specific to a transcriptional state or spatial location are pivotal in responses to treatment with the CDK4/6 inhibitor, Palbociclib. Our analysis reveals that SHH tumour in the mouse brain contains multiple malignant transcriptional states, recapitulating the extent of intratumoural cellular diversity identified in primary human SHH MB. Our study offers new insight into the previously described features of CDK4/6 inhibition in MB, with Palbociclib treatment inducing neuronal differentiation across all remaining cell types comprising the bulk of the SHH patient-derived orthotropic xenograft model. This study is, to the best of our knowledge, the first spatially resolved gene expression atlas of SHH PDOX MB and acts as proof-of-principle for the use of ST-seq in identifying spatially-organised tumour heterogeneity of MB.

2022-06-16 | E-MTAB-11720 | biostudies-arrayexpress

Sonic Hedgehog subgroup medulloblastomas

Project description:Sonic Hedgehog subgroup medulloblastomas

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Project description:Physiologically, trophoblast progenitor cells differentiate into placental villous cytotrophoblast cells (CTBs). CTBs either differentiate into invasive lineage to yields extravillous cytotrophoblast cells (EVTs), or undergo cell fusion lineage to yields syncytiotrophoblast cells (STBs)，Sonic hedgehog (Shh) together with indian hedgehog (Ihh) and desert hedgehog (Dhh) consist of ligand of hedgehog signaling pathway, which plays pivotal roles in regulating cell proliferation, cell differentiation, organogenesis and development, even involving in tumorigenesis and progression. previous study had summarized and indicatedthat hedgehog proteins played important roles in regulating hematopoiesis, vasculogenesis and angiogenesis during embryogenesis and development. Herein, we investigate the effect of the Sonic Hedgehog morphogen inhibitor Cyclopamine on JAR cells

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KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis

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Spatial transcriptomic analysis of Sonic hedgehog medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition.

Project description:BackgroundMedulloblastoma (MB) is a malignant tumour of the cerebellum which can be classified into four major subgroups based on gene expression and genomic features. Single-cell transcriptome studies have defined the cellular states underlying each MB subgroup; however, the spatial organisation of these diverse cell states and how this impacts response to therapy remains to be determined.MethodsHere, we used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of MB and show that cells specific to a transcriptional state or spatial location are pivotal for CDK4/6 inhibitor, Palbociclib, treatment response. We integrated spatial gene expression with histological annotation and single-cell gene expression data from MB, developing an analysis strategy to spatially map cell type responses within the hybrid system of human and mouse cells and their interface within an intact brain tumour section.ResultsWe distinguish neoplastic and non-neoplastic cells within tumours and from the surrounding cerebellar tissue, further refining pathological annotation. We identify a regional response to Palbociclib, with reduced proliferation and induced neuronal differentiation in both treated tumours. Additionally, we resolve at a cellular resolution a distinct tumour interface where the tumour contacts neighbouring mouse brain tissue consisting of abundant astrocytes and microglia and continues to proliferate despite Palbociclib treatment.ConclusionsOur data highlight the power of using spatial transcriptomics to characterise the response of a tumour to a targeted therapy and provide further insights into the molecular and cellular basis underlying the response and resistance to CDK4/6 inhibitors in SHH MB.

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Sonic hedgehog Activation Restores Interneurons and Cognitive Function in Newborns with Intraventricular Hemorrhage

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Project description:KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis [ATAC-seq]

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KMT2D suppresses Sonic Hedgehog-driven medulloblastoma progression and metastasis [RNA-seq]

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Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model

Project description:The causative role of activated Hedgehog signaling in liver fibrosis was investigated in vivo. Using hydrodynamics-based transfection, a transgenic mouse model has been developed that expresses Sonic Hedgehog (SHH), a ligand for Hedgehog signaling, in the liver. Levels of hepatic fibrosis and fibrosis-related gene expression were assessed in the model.

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