Drug and single-cell gene expression integration identifies sensitive and resistant glioblastoma cell populations
Glioblastoma (GBM) remains the most common and lethal adult malignant primary brain cancer with few treatment options. A significant issue hindering GBM therapeutic development is intratumor heterogeneity and plasticity. GBM tumors contain neoplastic cells within a fluid spectrum of diverse transcriptional states. Identifying effective therapeutics requires a platform that predicts the differential sensitivity and resistance of these states to various treatments. Here, we develop scFOCAL (Single-Cell Framework for -Omics Connectivity and Analysis via L1000), to quantify the cellular drug sensitivity and resistance landscape. Using single-cell RNA sequencing of newly diagnosed and recurrent GBM tumors, we identify compounds from the LINCS L1000 database with transcriptional response signatures selectively discordant with distinct GBM cell states, and leverage this capability to predict combination synergy. We validate the significance of these findings in vitro, ex vivo, and in vivo, and identify a combination of an OLIG2 inhibitor and Depatux-M for the treatment of GBM. Our studies suggest that scFOCAL identifies cell states that are sensitive and resistant to targeted therapies in GBM using a measure of cell and drug connectivity, which can be applied to identify new synergistic combinations.
Authors
- Winston Walters
- Matthew D’Antuono (ORCID: https://orcid.org/0000-0002-1837-7004)
- Stephan C. Schürer (ORCID: https://orcid.org/0000-0001-7180-0978)
- Jann Nagina Sarkaria (ORCID: https://orcid.org/0000-0001-7489-4885)
- Alexandre Wojcinski (ORCID: https://orcid.org/0000-0002-5141-8568)
- Grace Baker
- Simon Kaeppeli (ORCID: https://orcid.org/0000-0003-4449-6952)
- Rithvik Veeramachaneni
- Gregory Stein (ORCID: https://orcid.org/0000-0002-3588-8834)
- Danielle M. Burgenske (ORCID: https://orcid.org/0000-0003-0014-5579)
- Nagi Ayad (ORCID: https://orcid.org/0009-0002-1994-3095)
- Mark G. Anderson (ORCID: https://orcid.org/0000-0002-3231-4296)
- Vasileios Stathias (ORCID: https://orcid.org/0000-0003-1986-5947)
- Edward B. Reilly (ORCID: https://orcid.org/0000-0003-1999-7501)
- Anna M. Jermakowicz (ORCID: https://orcid.org/0000-0003-3271-051X)
- Anatol Oleksijew
- Ricardo J. Komotar (ORCID: https://orcid.org/0000-0002-7626-8869)
- Santosh Kesari (ORCID: https://orcid.org/0000-0003-3772-6000)
- Michael E. Ivan (ORCID: https://orcid.org/0000-0002-4798-4989)
- Robert K. Suter (ORCID: https://orcid.org/0000-0002-3335-8426)
- L.G. Zhang
- Lidia Ruíz (ORCID: https://orcid.org/0000-0002-8918-9158)
- Pravallika Palwai
- M de la Fuente
- Rishika Chowdary (ORCID: https://orcid.org/0000-0002-9090-5916)
- Madison Sharp
- Maria Cepero
- Sion Ll. Williams
Institutions
- University of Miami (US)
- Georgetown University (US)
- Georgetown University Medical Center (US)
- AbbVie (United States) (US)
- Saint John's Health Center (US)
- Mayo Clinic in Arizona (US)
- Arena Pharmaceuticals (United States) (US)
- Sylvester Comprehensive Cancer Center (US)
- Neurological Surgery (US)
- University Foot & Ankle Institute (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-07
- DOI
- https://doi.org/10.1038/s41467-025-67783-5
- Citations
- 1
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 22.24
Funders
- National Science Foundation
- University of Miami
- Georgetown University
- Sylvester Comprehensive Cancer Center, University of Miami Health Systems
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- Office of Advanced Cyberinfrastructure