Related Experiment Video
Updated: Mar 10, 2026
Isolation, Enrichment, and Maintenance of Medulloblastoma Stem Cells
Published on: September 1, 2010
Functional Genomics Identifies Tis21-Dependent Mechanisms and Putative Cancer Drug Targets Underlying Medulloblastoma
Giulia Gentile1, Manuela Ceccarelli2, Laura Micheli2
1Institute of Neurological Sciences, National Research Council Catania, Italy.
Abstract:
We have recently generated a novel medulloblastoma (MB) mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+/-/Tis21 ). Its main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs). By genomic analysis of GCPs in vivo, we identified as drug target and major responsible of this defect the down-regulation of the promigratory chemokine Cxcl3. Consequently, the GCPs remain longer in the cerebellum proliferative area, and the MB frequency is enhanced. Here, we further analyzed the genes deregulated in a Tis21-dependent manner (Patched1+/-/Tis21 wild-type vs. Ptch1+/-/Tis21 knockout), among which are a number of down-regulated tumor inhibitors and up-regulated tumor facilitators, focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets. The data analysis using bioinformatic tools revealed: (i) a link between the Shh signaling and the Tis21-dependent impairment of the GCPs migration, through a Shh-dependent deregulation of the clathrin-mediated chemotaxis operating in the primary cilium through the Cxcl3-Cxcr2 axis; (ii) a possible lineage shift of Shh-type GCPs toward retinal precursor phenotype, i.e., the neural cell type involved in group 3 MB; (iii) the identification of a subset of putative drug targets for MB, involved, among the others, in the regulation of Hippo signaling and centrosome assembly. Finally, our findings define also the role of Tis21 in the regulation of gene expression, through epigenetic and RNA processing mechanisms, influencing the fate of the GCPs.
Insights
Loss of Tis21 impairs cerebellar precursor cell migration in a novel medulloblastoma model, linked to Cxcl3 down-regulation and Shh pathway activation. This identifies new drug targets for medulloblastoma.
Area of Science:
- Neuro-oncology
- Developmental Neuroscience
- Molecular Biology
Background:
- Medulloblastoma (MB) is a pediatric brain tumor with diverse molecular subtypes.
- The Shh signaling pathway is frequently activated in MB, driving tumor growth.
- Tis21 acts as a tumor suppressor, but its role in MB pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of Tis21 in Shh-driven medulloblastoma.
- To identify molecular mechanisms underlying cerebellar granule precursor cell (GCP) migration defects in a novel MB mouse model.
- To discover novel therapeutic targets for medulloblastoma.
Main Methods:
- Generation of a novel mouse model (Patched1+/-/Tis21 knockout) with activated Shh signaling and Tis21 deficiency.
- Genomic analysis of GCPs to identify deregulated genes and pathways.
- Bioinformatic analysis to link Shh signaling, Tis21, GCP migration, and tumorigenesis.
Main Results:
- Tis21 deficiency impairs GCP migration by down-regulating the promigratory chemokine Cxcl3, linked to the Shh pathway and clathrin-mediated chemotaxis via the Cxcl3-Cxcr2 axis.
- A potential lineage shift of GCPs towards a retinal precursor phenotype was observed, relevant to group 3 MB.
- Several putative drug targets, including those regulating Hippo signaling and centrosome assembly, were identified.
Conclusions:
- Tis21 plays a crucial role in regulating GCP migration and preventing medulloblastoma development.
- The Shh pathway and Tis21 interact to control GCP migration through the Cxcl3-Cxcr2 axis.
- This study identifies novel therapeutic strategies and drug targets for medulloblastoma, particularly Shh-driven subtypes.
More Related Videos
05:10Intracranial Orthotopic Allografting of Medulloblastoma Cells in Immunocompromised Mice
Published on: October 3, 2010
10:58Transposon Mediated Integration of Plasmid DNA into the Subventricular Zone of Neonatal Mice to Generate Novel Models of Glioblastoma
Published on: February 22, 2015
Related Concept Videos
02:33Hedgehog Signaling Pathway
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:23Abnormal Proliferation
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...