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Elevated Kir2.1/nuclear N2ICD defines a highly malignant subtype of non-WNT/SHH medulloblastomas.
- Source :
-
Signal transduction and targeted therapy [Signal Transduct Target Ther] 2022 Mar 11; Vol. 7 (1), pp. 72. Date of Electronic Publication: 2022 Mar 11. - Publication Year :
- 2022
-
Abstract
- Medulloblastoma (MB) is one of the most common childhood malignant brain tumors (WHO grade IV), traditionally divided into WNT, SHH, Group 3, and Group 4 subgroups based on the transcription profiles, somatic DNA alterations, and clinical outcomes. Unlike WNT and SHH subgroup MBs, Group 3 and Group 4 MBs have similar transcriptomes and lack clearly specific drivers and targeted therapeutic options. The recently revised WHO Classification of CNS Tumors has assigned Group 3 and 4 to a provisional non-WNT/SHH entity. In the present study, we demonstrate that Kir2.1, an inwardly-rectifying potassium channel, is highly expressed in non-WNT/SHH MBs, which promotes tumor cell invasion and metastasis by recruiting Adam10 to enhance S2 cleavage of Notch2 thereby activating the Notch2 signaling pathway. Disruption of the Notch2 pathway markedly inhibited the growth and metastasis of Kir2.1-overexpressing MB cell-derived xenograft tumors in mice. Moreover, Kir2.1 <superscript>high</superscript> /nuclear N2ICD <superscript>high</superscript> MBs are associated with the significantly shorter lifespan of the patients. Thus, Kir2.1 <superscript>high</superscript> /nuclear N2ICD <superscript>high</superscript> can be used as a biomarker to define a novel subtype of non-WNT/SHH MBs. Our findings are important for the modification of treatment regimens and the development of novel-targeted therapies for non-WNT/SHH MBs.<br /> (© 2022. The Author(s).)
- Subjects :
- Animals
Child
Hedgehog Proteins genetics
Hedgehog Proteins metabolism
Humans
Mice
Mutation
Potassium Channels, Inwardly Rectifying
Signal Transduction
Cerebellar Neoplasms genetics
Cerebellar Neoplasms metabolism
Cerebellar Neoplasms pathology
Medulloblastoma genetics
Medulloblastoma metabolism
Medulloblastoma pathology
Subjects
Details
- Language :
- English
- ISSN :
- 2059-3635
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Signal transduction and targeted therapy
- Publication Type :
- Academic Journal
- Accession number :
- 35273141
- Full Text :
- https://doi.org/10.1038/s41392-022-00890-7