MSI1 Promotes the Expression of the GBM Stem Cell Marker CD44 by Impairing miRNA-Dependent Degradation.

Rebecca Pötschke,Markus Glaß,Jacob Haase,Sebastian Simmermacher,Luiz O F Penalva,Stefan Hüttelmaier,Claudia Misiak,Caspar D Kühnöl

doi:10.3390/cancers12123654

Abstract

Simple SummaryGlioblastoma (GBM) is the most lethal brain tumor with a median survival rate of approximately 14 months. GBM patients commonly suffer from tumor recurrence, indicating that populations of chemo/radio-resistant stem cell-like tumor cells survive treatments. Here we reveal that the neuronal stem cell marker Musashi1 (MSI1) is highly expressed in primary GBM and recurrences. We identify a novel regulatory role of MSI1 in GBM-derived cell lines and patient-derived tumorspheres, the enhancement of stemness marker expression, here demonstrated for CD44. Furthermore, we provide a rationale for MSI1-centered therapeutic targeting strategies to improve treatment options of this chemo/radio-resistant malignancy.The stem cell marker Musashi1 (MSI1) is highly expressed during neurogenesis and in glioblastoma (GBM). MSI1 promotes self-renewal and impairs differentiation in cancer and non-malignant progenitor cells. However, a comprehensive understanding of its role in promoting GBM-driving networks remains to be deciphered. We demonstrate that MSI1 is highly expressed in GBM recurrences, an oncologist’s major defiance. For the first time, we provide evidence that MSI1 promotes the expression of stem cell markers like CD44, co-expressed with MSI1 within recurrence-promoting cells at the migrating front of primary GBM samples. With GBM cell models of pediatric and adult origin, including isolated primary tumorspheres, we show that MSI1 promotes stem cell-like characteristics. Importantly, it impairs CD44 downregulation in a 3′UTR- and miRNA-dependent manner by controlling mRNA turnover. This regulation is disturbed by the previously reported MSI1 inhibitor luteolin, providing further evidence for a therapeutic target potential of MSI1 in GBM treatment.

Highlights

Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor (WHO grade IV glioma), with a median survival rate of approximately 14 months
By evaluating scRNA-seq data, we show that MSI1 and CD44 mRNAs are co-expressed at the invasive front of patient-derived GBM samples in single neoplastic cell populations [18]
In agreement with the proposed role of MSI1 in glioma-initiating stem or progenitor cells, its mRNA expression was found comparably high in tumor recurrences (Figure 1B) [19,21]

Summary

Introduction

Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor (WHO grade IV glioma), with a median survival rate of approximately 14 months. GBM show aggressive invasion into surrounding tissues, but rarely metastasize to distant organs [1]. GBM patients commonly suffer from tumor recurrence, indicating that populations of radio- and chemoresistant tumor cells survive treatments. These cells are likely GBM cancer stem cells (GBM-CSCs) [2]. By investigating single-cell RNA sequencing data (scRNA-seq), besides neurodevelopmental lineages, the existence of GBM-CSCs have been validated most recently [3]. These cells usually are identified by expressing

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