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Original Article
- Single-Cell Heterogeneity of EGFR Pathway Is Linked to Unique Signatures of Drug Response and Malignancy in Patient Derived Glioblastoma Stem Cells
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Michael D. Masterman-Smith1,2,3
, Nicholas A. Graham4,5, Eduard H. Panosyan6,7, Jack Mottahedeh8, Eric R. Samuels9, Araceli Nunez10, Tiffany Phillips11, Meeryo Choe6,12, Timothy F. Cloughesy6,12, Jorge A. Lazareff7,13, Linda M. Liau13, William H. Yong14, Thomas G. Graeber15,16, Harley I. Kornblum7,12,16, Ming-Fei Lang17, Yanzhao Li18
, Jing Sun1,19
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DOI: https://doi.org/10.4143/crt.2024.859 [Accepted]
Published online: January 7, 2025
1The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
2Rapid Acceleration of Diagnostics (RADx) COVID-19 Response Program, U.S. National Institutes of Health/National Institutes of Biomedical Imaging and Bioengineering, Bethesda, MD, USA
3Creative Sciences, Inc., Los Angels, CA, USA
4Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA
5Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
6Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
7Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
8Department of Psychiatry, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
9Abbvie Inc., Irvine, CA, USA
10School of Nursing, University of California at Los Angeles, CA, USA
11Samuel Oschin Comprehensive Cancer Center, Cedars Sinai Medical Center, Los Angeles, CA, USA
12Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
13Department of Neurosurgery, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
14Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
15Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
16California NanoSystems Institute, University of California at Los Angeles, CA, USA
17College of Medicine, Dalian Key Laboratory of Oligosaccharide Recombination and Recombinant Protein Modification, Dalian University, Dalian, China
18Department of Neurosurgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
19College of Environmental and Chemical Engineering, Dalian University, Dalian, China
2Rapid Acceleration of Diagnostics (RADx) COVID-19 Response Program, U.S. National Institutes of Health/National Institutes of Biomedical Imaging and Bioengineering, Bethesda, MD, USA
3Creative Sciences, Inc., Los Angels, CA, USA
4Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA
5Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
6Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
7Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
8Department of Psychiatry, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
9Abbvie Inc., Irvine, CA, USA
10School of Nursing, University of California at Los Angeles, CA, USA
11Samuel Oschin Comprehensive Cancer Center, Cedars Sinai Medical Center, Los Angeles, CA, USA
12Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
13Department of Neurosurgery, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
14Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
15Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA
16California NanoSystems Institute, University of California at Los Angeles, CA, USA
17College of Medicine, Dalian Key Laboratory of Oligosaccharide Recombination and Recombinant Protein Modification, Dalian University, Dalian, China
18Department of Neurosurgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
19College of Environmental and Chemical Engineering, Dalian University, Dalian, China
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Corresponding author:
Yanzhao Li
Tel: 86-411-62893000 Email: changzhiliyanzhao@126.com
Jing Sun
Tel: 86-411-87402284 Email: sunjing@dlu.edu.cn
Received: 4 September 2024 • Accepted: 6 January 2025
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Abstract
Purpose
In glioblastoma, the therapeutically intractable and resistant phenotypes can be derived from glioma stem cells, which often have different underlying mechanisms from non-stem glioma cells. Aberrant signaling across the EGFR-PTEN-AKT-mTOR pathways have been shown as common drivers of glioblastoma. Revealing the inter and intra-cellular heterogeneity within glioma stem cell populations in relations to signaling patterns through these pathways may be key to precision diagnostic and therapeutic targeting of these cells.
Materials and Methods
Single cell parallel proteomic heterogeneity profiling of the EGFR-PTEN-AKT-mTOR pathways was conducted in a panel of fifteen glioma stem cell models derived from patient glioblastoma biopsies.
Results
The analysis included 59,464 data points from 14,866 cells and identified forty-nine molecularly distinct signaling phenotypes. High content bioinformatics resolved two unique patient clusters diverging on EGFR expression and AKT/TORC1 activation. Phenotypic validation indicated drug responsive phenotypes to EGFR blocking in the high EGFR expressing cluster with lower tumor initiating potential in comparison to the AKT/TORC1 activated cluster. High EGFR expression trended with improved patient prognosis while AKT/TORC1 activated samples trended with poorer patient outcomes. Genetic heterogeneity was observed in both clusters with proneural, classical and mesenchymal subtypes observed.
Conclusion
Quantitative single cell heterogeneity profiling reveals divergent EGFR-PTEN-AKT-mTOR pathways of patient derived glioma stem cells, which would inform future research and personalized therapeutic strategies.
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