Polycomb group gene BMI1 controls invasion of medulloblastoma cells and inhibits BMP-regulated cell adhesion.
BACKGROUND
Medulloblastoma is the most common intracranial childhood malignancy and a genetically heterogeneous disease. Despite recent advances, current therapeutic approaches are still associated with high morbidity and mortality. Recent molecular profiling has suggested the stratification of medulloblastoma from one single disease into four distinct subgroups namely: WNT Group (best prognosis), SHH Group (intermediate prognosis), Group 3 (worst prognosis) and Group 4 (intermediate prognosis). BMI1 is a Polycomb group repressor complex gene overexpressed across medulloblastoma subgroups but most significantly in Group 4 tumours. Bone morphogenetic proteins are morphogens belonging to TGF-β superfamily of growth factors, known to inhibit medulloblastoma cell proliferation and induce apoptosis.


RESULTS
Here we demonstrate that human medulloblastoma of Group 4 characterised by the greatest overexpression of BMI1, also display deregulation of cell adhesion molecules. We show that BMI1 controls intraparenchymal invasion in a novel xenograft model of human MB of Group 4, while in vitro assays highlight that cell adhesion and motility are controlled by BMI1 in a BMP dependent manner.


CONCLUSIONS
BMI1 controls MB cell migration and invasion through repression of the BMP pathway, raising the possibility that BMI1 could be used as a biomarker to identify groups of patients who may benefit from a treatment with BMP agonists.
Ashirwad
A
Merve
Adrian M
AM
Dubuc
Xinyu
X
Zhang
Marc
M
Remke
Patricia A
PA
Baxter
Xiao-Nan
XN
Li
Michael D
MD
Taylor
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK. s.marino@qmul.ac.uk.
Silvia
S
Marino
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D066298:In Vitro Techniques; D008527:Medulloblastoma / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009924:Organ Culture Techniques; D063150:Polycomb Repressive Complex 1 / Q000235:genetics*; D014183:Transplantation, Heterologous
C069077:BMI1 protein, human; D019485:Bone Morphogenetic Proteins; D015815:Cell Adhesion Molecules; C013065:cell aggregation factors; D063150:Polycomb Repressive Complex 1