Nuclear Glycoprotein A Repetitions Predominant (GARP) Is a Common Trait of Glioblastoma Stem-like Cells and Correlates with Poor Survival in Glioblastoma Patients
by
, ,
Niklas Zimmer
1,†, 
Emily R. Trzeciak
1,†, 
Andreas Müller
2,3,
Philipp Licht
1,
Bettina Sprang
2,3,
Petra Leukel
4,
Volker Mailänder
1,5,
Clemens Sommer
4,
Florian Ringel
2,
Jochen Tuettenberg
6,
Ella Kim
2,3,‡ and
Andrea Tuettenberg
1,5,*,‡ 1
Department of Dermatology, University Medical Center Mainz, 55131 Mainz, Germany
2
Department of Neurosurgery, University Medical Center Mainz, 55131 Mainz, Germany
3
Laboratory of Experimental Neurooncology, University Medical Center Mainz, 55131 Mainz, Germany
4
Institute of Neuropathology, University Medical Center Mainz, 55131 Mainz, Germany
5
Research Center for Immunotherapy, University Medical Center Mainz, 55131 Mainz, Germany
6
Department of Neurosurgery, SHG-Klinikum Idar-Oberstein, 55743 Idar-Oberstein, Germany
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
Joint Senior Authors.
Cancers 2023, 15(24), 5711; https://doi.org/10.3390/cancers15245711
Submission received: 20 October 2023
/
Revised: 17 November 2023
/
Accepted: 1 December 2023
/
Published: 5 December 2023
(This article belongs to the Special Issue Targeting Human Glioblastoma Stem-Like Cells (GSCs))
Simple Summary
Glioblastoma (GB) is the most common primary brain tumor in adults, but it remains incurable due to its high degree of therapy resistance. Glioblastoma stem-like cells (GSCs) are believed to drive the initiation, progression, and therapy resistance of GB, making them an ideal therapeutic target to improve patient outcomes. However, due to their heterogeneity, there are no universal markers to identify GSCs. We evaluated GARP as a novel marker for GSCs and found that GARP is more stably and uniformly expressed by human GSCs, across cellular states and disease stages, than the commonly used GSC marker, CD133. Additionally, we showed that GARP is intranuclearly localized in GSCs, and we are the first to show that nuclear GARP levels (GARPNU+) are associated with poor patient survival. Our findings indicate that GARP/GARPNU+ expression is an improved marker for GSCs and suggest a potential application of GARP as a prognostic biomarker for GB.
Abstract
Glioblastoma (GB) is notoriously resistant to therapy. GB genesis and progression are driven by glioblastoma stem-like cells (GSCs). One goal for improving treatment efficacy and patient outcomes is targeting GSCs. Currently, there are no universal markers for GSCs. Glycoprotein A repetitions predominant (GARP), an anti-inflammatory protein expressed by activated regulatory T cells, was identified as a possible marker for GSCs. This study evaluated GARP for the detection of human GSCs utilizing a multidimensional experimental design that replicated several features of GB: (1) intratumoral heterogeneity, (2) cellular hierarchy (GSCs with varied degrees of self-renewal and differentiation), and (3) longitudinal GSC evolution during GB recurrence (GSCs from patient-matched newly diagnosed and recurrent GB). Our results indicate that GARP is expressed by GSCs across various cellular states and disease stages. GSCs with an increased GARP expression had reduced self-renewal but no alterations in proliferative capacity or differentiation commitment. Rather, GARP correlated inversely with the expression of GFAP and PDGFR-α, markers of astrocyte or oligodendrocyte differentiation. GARP had an abnormal nuclear localization (GARPNU+) in GSCs and was negatively associated with patient survival. The uniformity of GARP/GARPNU+ expression across different types of GSCs suggests a potential use of GARP as a marker to identify GSCs.
Keywords:
GARP; nuclear GARP; GARPNU+; LRRC32; glioblastoma; glioblastoma stem-like cells
