KMT2D Suppresses Sonic Hedgehog-driven Medulloblastoma Progression and Metastasis

Overview

Journal iScience

Publisher Cell Press

Date 2023 Oct 12

PMID 37822508

Authors

Reeti Mayur Sanghrajka

Richard Koche

Hector Medrano

Salsabiel El Nagar

Daniel N Stephen

Zhimin Lao

N Sumru Bayin

Kai Ge

Alexandra L Joyner

Affiliations

Soon will be listed here.

Abstract

The major cause of treatment failure and mortality among medulloblastoma patients is metastasis intracranially or along the spinal cord. The molecular mechanisms driving tumor metastasis in Sonic hedgehog-driven medulloblastoma (SHH-MB) patients, however, remain largely unknown. In this study we define a tumor suppressive role of (), a gene frequently mutated in the most metastatic β-subtype. Strikingly, genetic mouse models of SHH-MB demonstrate that heterozygous loss of in conjunction with activation of the SHH pathway causes highly penetrant disease with decreased survival, increased hindbrain invasion and spinal cord metastasis. Loss of attenuates neural differentiation and shifts the transcriptional/chromatin landscape of primary and metastatic tumors toward a decrease in differentiation genes and tumor suppressors and an increase in genes/pathways implicated in advanced stage cancer and metastasis (TGFβ, Notch, , , and ). Thus, secondary heterozygous mutations likely have prognostic value for identifying SHH-MB patients prone to develop metastasis.

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