Single-cell based elucidation of molecularly-distinct glioblastoma states and drug sensitivity
Abstract Glioblastoma heterogeneity and plasticity remain controversial, with proposed subtypes representing the average of highly heterogeneous admixtures of independent transcriptional states. Single-cell, protein-activity-based analysis allowed full quantification of >6,000 regulatory and signaling proteins, thus providing a previously unattainable single-cell characterization level. This helped identify four novel, molecularly distinct subtypes that successfully harmonize across multiple GBM datasets, including previously published bulk and single-cell profiles and single cell profiles from seven orthotopic PDX models, representative of prior subtype diversity. GBM is thus characterized by the plastic coexistence of single cells in two mutually-exclusive developmental lineages, with additional stratification provided by their proliferative potential. Consistently, all previous subtypes could be recapitulated by single-cell mixtures drawn from newly identified states. Critically, drug sensitivity was predicted and validated as highly state-dependent, both in single-cell assays from patient-derived explants and in PDX models, suggesting that successful treatment requires combinations of multiple drugs targeting these distinct tumor states.Significance We propose a new, 4-subtype GBM classification, which harmonizes across bulk and single-cell datasets. Single-cell mixtures from these subtypes effectively recapitulate all prior classifications, suggesting that the latter are a byproduct of GBM heterogeneity. Finally, we predict single-cell level activity of three clinically-relevant drugs, and validate them in patient-derived explant..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 21. Sept. Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ding, Hongxu [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
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| doi: |
10.1101/675439 |
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XBI000547751 |
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| 520 | |a Abstract Glioblastoma heterogeneity and plasticity remain controversial, with proposed subtypes representing the average of highly heterogeneous admixtures of independent transcriptional states. Single-cell, protein-activity-based analysis allowed full quantification of >6,000 regulatory and signaling proteins, thus providing a previously unattainable single-cell characterization level. This helped identify four novel, molecularly distinct subtypes that successfully harmonize across multiple GBM datasets, including previously published bulk and single-cell profiles and single cell profiles from seven orthotopic PDX models, representative of prior subtype diversity. GBM is thus characterized by the plastic coexistence of single cells in two mutually-exclusive developmental lineages, with additional stratification provided by their proliferative potential. Consistently, all previous subtypes could be recapitulated by single-cell mixtures drawn from newly identified states. Critically, drug sensitivity was predicted and validated as highly state-dependent, both in single-cell assays from patient-derived explants and in PDX models, suggesting that successful treatment requires combinations of multiple drugs targeting these distinct tumor states.Significance We propose a new, 4-subtype GBM classification, which harmonizes across bulk and single-cell datasets. Single-cell mixtures from these subtypes effectively recapitulate all prior classifications, suggesting that the latter are a byproduct of GBM heterogeneity. Finally, we predict single-cell level activity of three clinically-relevant drugs, and validate them in patient-derived explant. | ||
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| 700 | 1 | |a Zhao, Wenting |e verfasserin |4 aut | |
| 700 | 1 | |a Subramaniam, Prem S. |e verfasserin |4 aut | |
| 700 | 1 | |a Bakken, Katrina K. |e verfasserin |4 aut | |
| 700 | 1 | |a He, Lihong |e verfasserin |4 aut | |
| 700 | 1 | |a Alvarez, Mariano J. |e verfasserin |4 aut | |
| 700 | 1 | |a Laise, Pasquale |e verfasserin |4 aut | |
| 700 | 1 | |a Paull, Evan O. |e verfasserin |4 aut | |
| 700 | 1 | |a Spinazzi, Eleonora F. |e verfasserin |4 aut | |
| 700 | 1 | |a Dovas, Athanassios |e verfasserin |4 aut | |
| 700 | 1 | |a Marie, Tamara |e verfasserin |4 aut | |
| 700 | 1 | |a Upadhyayula, Pavan |e verfasserin |4 aut | |
| 700 | 1 | |a Cruz, Filemon Dela |e verfasserin |4 aut | |
| 700 | 1 | |a Diolaiti, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Kung, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Bruce, Jeffrey N. |e verfasserin |4 aut | |
| 700 | 1 | |a Canoll, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Sims, Peter A. |e verfasserin |4 aut | |
| 700 | 1 | |a Sarkaria, Jann N. |e verfasserin |4 aut | |
| 700 | 1 | |a Califano, Andrea |e verfasserin |4 aut | |
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