NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma.

Fiaschetti, Giulio; Schroeder, Christina; Castelletti, Deborah; Arcaro, Alexandre; Westermann, Frank; Baumgartner, Martin; Shalaby, Tarek; Grotzer, Michael A (2014). NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma. Acta neuropathologica communications, 2, p. 39. BioMed Central 10.1186/2051-5960-2-39

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Medulloblastoma (MB), the most common pediatric malignant brain cancer, typically arises as pathological result of deregulated developmental pathways, including the NOTCH signaling cascade. Unlike the evidence supporting a role for NOTCH receptors in MB development, the pathological functions of NOTCH ligands remain largely unexplored. By examining the expression in large cohorts of MB primary tumors, and in established in vitro MB models, this research study demonstrates that MB cells bear abnormal levels of distinct NOTCH ligands. We explored the potential association between NOTCH ligands and the clinical outcome of MB patients, and investigated the rational of inhibiting NOTCH signaling by targeting specific ligands to ultimately provide therapeutic benefits in MB. The research revealed a significant over-expression of ligand JAG1 in the vast majority of MBs, and proved that JAG1 mediates pro-proliferative signals via activation of NOTCH2 receptor and induction of HES1 expression, thus representing an attractive therapeutic target. Furthermore, we could identify a clinically relevant association between ligand JAG2 and the oncogene MYC, specific for MYC-driven Group 3 MB cases. We describe for the first time a mechanistic link between the oncogene MYC and NOTCH pathway in MB, by identifying JAG2 as MYC target, and by showing that MB cells acquire induced expression of JAG2 through MYC-induced transcriptional activation. Finally, the positive correlation of MYC and JAG2 also with aggressive anaplastic tumors and highly metastatic MB stages suggested that high JAG2 expression may be useful as additional marker to identify aggressive MBs.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hämatologie / Onkologie (Pädiatrie)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hämatologie / Onkologie (Pädiatrie)

UniBE Contributor:

Arcaro, Alexandre

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2051-5960

Publisher:

BioMed Central

Language:

English

Submitter:

André Schaller

Date Deposited:

05 Feb 2015 11:17

Last Modified:

05 Feb 2015 11:17

Publisher DOI:

10.1186/2051-5960-2-39

PubMed ID:

24708907

BORIS DOI:

10.7892/boris.62496

URI:

https://boris.unibe.ch/id/eprint/62496

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