Meningioma cells express primary cilia but do not transduce ciliary Hedgehog signals

Abrar Choudhury,Vikas Daggubati,David R Raleigh,Ursula E Lang,Melike Pekmezci,Sarah Findakly

doi:10.1186/s40478-020-00994-7

Abstract

Meningiomas are the most common primary intracranial tumors, but treatment options for meningioma patients are limited due to incomplete understanding of tumor biology. A small percentage of meningiomas harbor somatic variants in the Hedgehog pathway, a conserved gene expression program that is essential for development and adult stem cell homeostasis. Hedgehog signals are transduced through primary cilia, and misactivation of the Hedgehog pathway is known to underlie cancer. Nevertheless, the mechanisms of Hedgehog signaling in meningioma are unknown. Here, we investigate mechanisms of ciliary Hedgehog signaling in meningioma using tissue microarrays containing 154 human meningioma samples, NanoString transcriptional profiling, primary meningioma cells, pharmacology, and CRISPR interference. Our results reveal that meningiomas of all grades can express primary cilia, but that cilia are less prevalent among anaplastic tumors. Moreover, we find that expression of Smoothened alleles that are oncogenic in other contexts fail to activate the Hedgehog transcriptional program or promote proliferation in primary meningioma cells. These data reveal that meningiomas can express the subcellular structure necessary for canonical Hedgehog signaling, but suggest that they do not transduce ciliary Hedgehog signals.

Highlights

Meningiomas arising from the lining of the central nervous system are the most common primary intracranial tumors [15]
To investigate mechanisms of Hedgehog signaling in meningioma, we created tissue microarrays comprised of 154 meningiomas from patients with comprehensive clinical follow-up data who were treated with standard therapies at a single institution from 2003 to 2012 [14]
We identified no differences in overall survival according to ciliary length or prevalence; no differences in ciliary length or SMO expression according to meningioma grade; no differences in SMO expression according to ciliary length; no differences in local freedom from recurrence according to ciliary length or SMO expression; no differences in ciliary length or prevalence according to patient sex, prior treatment, or meningioma location; and no associations between ciliary length or prevalence and meningioma size or Mindbomb E3 Ubiquitin Protein Ligase 1 (MIB1) labeling index (Supplementary Table S1)

Summary

Introduction

Meningiomas arising from the lining of the central nervous system are the most common primary intracranial tumors [15]. The World Health Organization (WHO) classifies meningiomas according to mitotic activity and histopathologic features associated with aggressive clinical behavior [13]. WHO grade I meningiomas have low mitotic activity and can be effectively treated with surgery and radiation [3]. High grade meningiomas, which account for 20–30% of cases, are a significant cause of neurologic morbidity and mortality [3]. There is an urgent, unmet need for new meningioma treatments.

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