A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma.

White White,Cain Cain,Remke Remke,Jayasekara Jayasekara,Gough Gough,Chen Chen,Watkins Watkins,Picard Picard

doi:10.3390/cancers11111702

Abstract

Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represent a major health care burden and have led to ongoing efforts to find effective targeted treatments. There is a well-recognized male bias in medulloblastoma diagnosis, although the mechanism remains unknown. Herein, we identify a sex-specific role for the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) in the Sonic Hedgehog (SHH) medulloblastoma subgroup. Specific deletion of Stat3 from granule cell precursors in a spontaneous mouse model of SHH medulloblastoma completely protects male, but not female mice from tumor initiation. Segregation of SHH medulloblastoma patients into high and low STAT3 expressing cohorts shows that low STAT3 expression correlates with improved overall survival in male patients. We observe sex specific changes in IL-10 and IL-6 expression and show that IL-6 stimulation enhances SHH-mediated gene transcription in a STAT3-dependent manner. Together these data identify STAT3 as a key molecule underpinning the sexual dimorphism in medulloblastoma.

Highlights

Medulloblastoma (MB) is the most common malignant pediatric brain tumor [1]
We performed an immunohistochemical analysis of Signal Transducer and Activator of Transcription 3 (STAT3) expression in the cerebellum of adult wild-type mice and in tumors formed in the Ptch1LacZ/+ mouse model of Sonic Hedgehog (SHH) MB in which exon 1 and 2 of the Ptch1 gene are replaced with a LacZ reporter resulting in loss of function [25]
We observed increased Stat3 expression stochastically distributed throughout SHH medulloblastoma tumors that arise from the granule cell layer

Summary

Introduction

Medulloblastoma (MB) is the most common malignant pediatric brain tumor [1]. Improvements in surgery, radiotherapy and chemotherapy have dramatically improved patient outcomes, but are associated with devastating impacts on normal development, with >90% of survivors requiring long-term special education services [2]. Characterization of the genomic, transcriptomic, epigenetic and proteomic landscape of MB have revealed that MB is not a single monolithic disease and is segregated into at least four disease subgroups: Wingless (WNT); Sonic Hedgehog (SHH); Group 3 and Group 4 [3,4,5]. Subgroups are distinguished by cell of origin, genetic drivers, demographics and prognosis [1,6]. This refined understanding of the disease is influencing patient care.

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