Genetic manipulation of adhesion GPCR CD97/ADGRE5 modulates invasion in patient-derived glioma stem cells
D G Eichberg1, T I Slepak2, A L Pascoini2
1Department of Neurosurgery, University of Miami Hospital, University of Miami, 1321 N.W. 14th Street, West Building, Suite 306, Miami, FL, 33125, USA. dge18@med.miami.edu.
Introduction:
Effective glioblastoma (GBM) treatment is limited by high invasiveness and heterogeneity. Current therapies target proliferating Glioma Stem Cell (GSC) subpopulations while sparing invading GSCs, which eventually engender tumor recurrence after treatment. Surface receptor CD97/ADRGE5 is associated with invasion and metastasis regulation in non-CNS cancers. Although CD97 expression level positively correlates with poor GBM patient prognosis, its role in this tumor is unclear.
Methods:
Here, we examined CD97 function in primary patient-derived GSCs (pdGSCs) obtained from five GBM tumors, belonging to three major genetic subtypes. We compared endogenous CD97 levels in pdGSCs to the corresponding patient MRI's radiographic invasion pattern aggressiveness. We manipulated CD97 levels in these pdGSCs by knockdown and overexpression and analyzed: (i) stem and subtype marker expression, (ii) in vitro invasive properties, and (iii) cell proliferation.
Results:
Endogenous CD97 levels in pdGSCs positively correlated with radiographic invasion pattern aggressiveness on patient MRIs, and in vitro invasion rate. CD97 knockdown decreased pdGSC invasion rates in vitro, most markedly in mesenchymal subtype pdGSCs, as well as classical subtype pdGSCs. Invasion rates in vitro increased after CD97 overexpression predominately in proneural subtype pdGSCs. In the pdGSC line with the lowest endogenous CD97 level, CD97 overexpression increased the proliferation rate almost threefold.
Conclusions:
For the first time in pdGSCs, we have shown that CD97 knockdown decreases and overexpression increases invasion rate in vitro. The effect of CD97 on invasion is pdGSC subtype-dependent. Future in vivo and mechanistic studies are needed for validation. Pharmacologic CD97 inhibitors should be identified, as they may potentially therapeutically diminish GBM invasion.
Insights
CD97 receptor influences glioblastoma invasion, with its effects varying by tumor subtype. Targeting CD97 may offer new therapeutic strategies for this aggressive brain cancer.
Area of Science:
- Neuro-oncology
- Cancer biology
- Molecular oncology
Background:
- Glioblastoma (GBM) treatment is challenged by invasive and heterogeneous tumor cells.
- Glioma Stem Cells (GSCs) drive tumor recurrence, evading current therapies.
- CD97 receptor's role in GBM invasion and prognosis requires elucidation.
Purpose of the Study:
- To investigate the function of CD97 in primary patient-derived GSCs (pdGSCs).
- To correlate CD97 levels with GBM invasion patterns and GSC subtype markers.
- To assess the impact of CD97 modulation on GSC invasion and proliferation.
Main Methods:
- Analyzed endogenous CD97 levels in pdGSCs from five GBM tumors.
- Correlated CD97 levels with radiographic invasion on patient MRIs.
- Utilized CD97 knockdown and overexpression in pdGSCs to study invasion and proliferation.
Main Results:
- CD97 levels positively correlated with GBM invasion aggressiveness in vitro and on MRIs.
- CD97 knockdown reduced invasion, particularly in mesenchymal and classical pdGSCs.
- CD97 overexpression increased invasion in proneural pdGSCs and proliferation in a subset of pdGSCs.
Conclusions:
- CD97 modulates GBM invasion in a subtype-dependent manner in pdGSCs.
- CD97 inhibition presents a potential therapeutic avenue to reduce GBM invasion.
- Further in vivo and mechanistic studies are warranted to validate these findings.
