Functional genomics identifies Tis21-dependent mechanisms and putative cancer drug targets underlying medulloblastoma shh-type development

Giulia Gentile, Manuela Ceccarelli, Laura Micheli, Felice Tirone, Sebastiano Cavallaro

Research output: Contribution to journalArticle

Abstract

We have recently generated a novel medulloblastoma (MB) mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+/-/Tis21KO). 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.

Original languageEnglish
Pages (from-to)1
Number of pages1
JournalFrontiers in Pharmacology
Volume7
Issue numberNOV
DOIs
Publication statusPublished - Nov 30 2016

Fingerprint

Medulloblastoma
Genomics
Pharmaceutical Preparations
Neoplasms
Phenotype
Centrosome
Clathrin
Cilia
Gene Expression Regulation
Chemotaxis
Computational Biology
Chemokines
Epigenomics
Cerebellum
Carcinogenesis
Down-Regulation
RNA
Genes

Keywords

  • Cerebellar precursor cell
  • Chemokines
  • Drug target
  • Medulloblastoma model
  • Neural migration
  • Primary cilium
  • Retina
  • Sonic Hedgehog

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Functional genomics identifies Tis21-dependent mechanisms and putative cancer drug targets underlying medulloblastoma shh-type development. / Gentile, Giulia; Ceccarelli, Manuela; Micheli, Laura; Tirone, Felice; Cavallaro, Sebastiano.

In: Frontiers in Pharmacology, Vol. 7, No. NOV, 30.11.2016, p. 1.

Research output: Contribution to journalArticle

Gentile, Giulia ; Ceccarelli, Manuela ; Micheli, Laura ; Tirone, Felice ; Cavallaro, Sebastiano. / Functional genomics identifies Tis21-dependent mechanisms and putative cancer drug targets underlying medulloblastoma shh-type development. In: Frontiers in Pharmacology. 2016 ; Vol. 7, No. NOV. pp. 1.
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