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

Abstract

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.

miR-140-5p inhibits human glioma cell growth and invasion by targeting JAG1

“…It has been demonstrated that JAG1 is overexpressed in various types of cancer, and it is involved in several aspects of tumor biology, including cell growth, apoptosis, cancer stem cell maintenance, epithelial-mesenchymal transition and metastasis (38). Fiaschetti et al (39) revealed that JAG1 is overexpressed in the majority of medulloblastoma (MB), and JAG1 is crucial in maintaining Notch-related pro-survival functions in MB cells (39). In the present study, JAG1 expression was demonstrated to be regulated by miR-140-5p in glioma cells.…”

The Ser/Thr kinase MAP4K4 drives c-Met-induced motility and invasiveness in a cell-based model of SHH medulloblastoma

“…All data used are accessible through the open access platform R2 for visualization and analysis of the microarray data ( http://r2.amc.nl ). The following datasets were used: Delattre 54 MAS 5.0 – u133p2 (54 MB samples), Gilbertson 76 MAS 5.0 – u133p2 (76 pediatric MB samples, PubMed link: 22722829), Kool 62 MAS 5.0 – u133p2 (62 human MB samples, PubMed link 18769486), Northcott 103 rma_sketch – huex10t (103 primary MB samples, PubMed link 20823417) and MAGIC 285 rma-sketch – hugene11t (285 primary MB samples, PubMed link 22832581) Analysis was performed as described in (Fiaschetti et al 2014 ). The nine normal cerebellum samples are from human subject aged as follows: Donor 1–25 year old male; donor 2–38 year old male; donor 3–39 year old female; donor 4–30 year old male; donor 5–35 year old male; donor 6–52 year old male; donor 7–50 year old female; donor 8–48 year old female; donor 9–53 year old female; donor 10–23 year old female.…”

Crosstalk between SHH and FGFR Signaling Pathways Controls Tissue Invasion in Medulloblastoma

“…HD-MBO3 [17] was generously provided by Till Milde (DKFZ, Germany). DAOY cells were cultured as described in [33]. DAOY Lifeact-enhanced green fluorescent protein LA-EGFP cells were produced by lentiviral transduction of DAOY cells with pLenti-LA-EGFP.…”