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Title: | Single-cell molecular profiling using ex vivo functional readouts fuels precision oncology in glioblastoma | Authors: | Panovska, Dena Nazari, Pouya Cole, Basiel Creemers, Pieter-Jan Derweduwe, Marleen Solie, Lien Van Gassen, Sofie Claeys, Annelies Verbeke, Tatjana Cohen, Elizabeth F. Tolstorukov, Michael Y. Saeys, Yvan van der Planken, David Bosisio, Francesca M. PUT, Eric BAMPS, Sven Clement, Paul M. Verfaillie, Michiel Sciot, Raf Ligon, Keith L. De Vleeschouwer, Steven Antoranz, Asier De Smet, Frederik |
Issue Date: | 2023 | Publisher: | SPRINGER BASEL AG | Source: | CELLULAR AND MOLECULAR LIFE SCIENCES, 80 (6) (Art N° 147) | Abstract: | BackgroundFunctional profiling of freshly isolated glioblastoma (GBM) cells is being evaluated as a next-generation method for precision oncology. While promising, its success largely depends on the method to evaluate treatment activity which requires sufficient resolution and specificity.MethodsHere, we describe the 'precision oncology by single-cell profiling using ex vivoreadouts of functionality' (PROSPERO) assay to evaluate the intrinsic susceptibility of high-grade brain tumor cells to respond to therapy. Different from other assays, PROSPERO extends beyond life/death screening by rapidly evaluating acute molecular drug responses at single-cell resolution.ResultsThe PROSPERO assay was developed by correlating short-term single-cell molecular signatures using mass cytometry by time-of-flight (CyTOF) to long-term cytotoxicity readouts in representative patient-derived glioblastoma cell cultures (n = 14) that were exposed to radiotherapy and the small-molecule p53/MDM2 inhibitor AMG232. The predictive model was subsequently projected to evaluate drug activity in freshly resected GBM samples from patients (n = 34). Here, PROSPERO revealed an overall limited capacity of tumor cells to respond to therapy, as reflected by the inability to induce key molecular markers upon ex vivo treatment exposure, while retaining proliferative capacity, insights that were validated in patient-derived xenograft (PDX) models. This approach also allowed the investigation of cellular plasticity, which in PDCLs highlighted therapy-induced proneural-to-mesenchymal (PMT) transitions, while in patients' samples this was more heterogeneous.ConclusionPROSPERO provides a precise way to evaluate therapy efficacy by measuring molecular drug responses using specific biomarker changes in freshly resected brain tumor samples, in addition to providing key functional insights in cellular behavior, which may ultimately complement standard, clinical biomarker evaluations. | Notes: | De Smet, F (corresponding author), Katholieke Univ Leuven, Dept Imaging & Pathol, Herestr 49, B-1032 Leuven, Belgium.; De Smet, F (corresponding author), Leuven Inst Single Cell Om LISCO, Leuven, Belgium. frederik.desmet@kuleuven.be |
Keywords: | Functional diagnostics;Glioblastoma;Ex vivo treatment;Single-cell;Precision medicine | Document URI: | http://hdl.handle.net/1942/40257 | ISSN: | 1420-682X | e-ISSN: | 1420-9071 | DOI: | 10.1007/s00018-023-04772-1 | ISI #: | 000986411400001 | Rights: | The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023 | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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