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Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma

Background: Inevitable recurrence after radiochemotherapy is the major problem in the treatment of glioblastoma, the most prevalent type of adult brain malignancy. Glioblastomas are notorious for a high degree of intratumor heterogeneity manifest through a diversity of cell types and molecular patte...

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Autores principales: Kim, Ella L., Sorokin, Maxim, Kantelhardt, Sven Rainer, Kalasauskas, Darius, Sprang, Bettina, Fauss, Julian, Ringel, Florian, Garazha, Andrew, Albert, Eugene, Gaifullin, Nurshat, Hartmann, Christian, Naumann, Nicole, Bikar, Sven-Ernö, Giese, Alf, Buzdin, Anton
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072286/
https://www.ncbi.nlm.nih.gov/pubmed/32102350
http://dx.doi.org/10.3390/cancers12020520
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author Kim, Ella L.
Sorokin, Maxim
Kantelhardt, Sven Rainer
Kalasauskas, Darius
Sprang, Bettina
Fauss, Julian
Ringel, Florian
Garazha, Andrew
Albert, Eugene
Gaifullin, Nurshat
Hartmann, Christian
Naumann, Nicole
Bikar, Sven-Ernö
Giese, Alf
Buzdin, Anton
author_facet Kim, Ella L.
Sorokin, Maxim
Kantelhardt, Sven Rainer
Kalasauskas, Darius
Sprang, Bettina
Fauss, Julian
Ringel, Florian
Garazha, Andrew
Albert, Eugene
Gaifullin, Nurshat
Hartmann, Christian
Naumann, Nicole
Bikar, Sven-Ernö
Giese, Alf
Buzdin, Anton
author_sort Kim, Ella L.
collection PubMed
description Background: Inevitable recurrence after radiochemotherapy is the major problem in the treatment of glioblastoma, the most prevalent type of adult brain malignancy. Glioblastomas are notorious for a high degree of intratumor heterogeneity manifest through a diversity of cell types and molecular patterns. The current paradigm of understanding glioblastoma recurrence is that cytotoxic therapy fails to target effectively glioma stem cells. Recent advances indicate that therapy-driven molecular evolution is a fundamental trait associated with glioblastoma recurrence. There is a growing body of evidence indicating that intratumor heterogeneity, longitudinal changes in molecular biomarkers and specific impacts of glioma stem cells need to be taken into consideration in order to increase the accuracy of molecular diagnostics still relying on readouts obtained from a single tumor specimen. Methods: This study integrates a multisampling strategy, longitudinal approach and complementary transcriptomic investigations in order to identify transcriptomic traits of recurrent glioblastoma in whole-tissue specimens of glioblastoma or glioblastoma stem cells. In this study, 128 tissue samples of 44 tumors including 23 first diagnosed, 19 recurrent and 2 secondary recurrent glioblastomas were analyzed along with 27 primary cultures of glioblastoma stem cells by RNA sequencing. A novel algorithm was used to quantify longitudinal changes in pathway activities and model efficacy of anti-cancer drugs based on gene expression data. Results: Our study reveals that intratumor heterogeneity of gene expression patterns is a fundamental characteristic of not only newly diagnosed but also recurrent glioblastomas. Evidence is provided that glioblastoma stem cells recapitulate intratumor heterogeneity, longitudinal transcriptomic changes and drug sensitivity patterns associated with the state of recurrence. Conclusions: Our results provide a transcriptional rationale for the lack of significant therapeutic benefit from temozolomide in patients with recurrent glioblastoma. Our findings imply that the spectrum of potentially effective drugs is likely to differ between newly diagnosed and recurrent glioblastomas and underscore the merits of glioblastoma stem cells as prognostic models for identifying alternative drugs and predicting drug response in recurrent glioblastoma. With the majority of recurrent glioblastomas being inoperable, glioblastoma stem cell models provide the means of compensating for the limited availability of recurrent glioblastoma specimens.
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spelling pubmed-70722862020-03-19 Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma Kim, Ella L. Sorokin, Maxim Kantelhardt, Sven Rainer Kalasauskas, Darius Sprang, Bettina Fauss, Julian Ringel, Florian Garazha, Andrew Albert, Eugene Gaifullin, Nurshat Hartmann, Christian Naumann, Nicole Bikar, Sven-Ernö Giese, Alf Buzdin, Anton Cancers (Basel) Article Background: Inevitable recurrence after radiochemotherapy is the major problem in the treatment of glioblastoma, the most prevalent type of adult brain malignancy. Glioblastomas are notorious for a high degree of intratumor heterogeneity manifest through a diversity of cell types and molecular patterns. The current paradigm of understanding glioblastoma recurrence is that cytotoxic therapy fails to target effectively glioma stem cells. Recent advances indicate that therapy-driven molecular evolution is a fundamental trait associated with glioblastoma recurrence. There is a growing body of evidence indicating that intratumor heterogeneity, longitudinal changes in molecular biomarkers and specific impacts of glioma stem cells need to be taken into consideration in order to increase the accuracy of molecular diagnostics still relying on readouts obtained from a single tumor specimen. Methods: This study integrates a multisampling strategy, longitudinal approach and complementary transcriptomic investigations in order to identify transcriptomic traits of recurrent glioblastoma in whole-tissue specimens of glioblastoma or glioblastoma stem cells. In this study, 128 tissue samples of 44 tumors including 23 first diagnosed, 19 recurrent and 2 secondary recurrent glioblastomas were analyzed along with 27 primary cultures of glioblastoma stem cells by RNA sequencing. A novel algorithm was used to quantify longitudinal changes in pathway activities and model efficacy of anti-cancer drugs based on gene expression data. Results: Our study reveals that intratumor heterogeneity of gene expression patterns is a fundamental characteristic of not only newly diagnosed but also recurrent glioblastomas. Evidence is provided that glioblastoma stem cells recapitulate intratumor heterogeneity, longitudinal transcriptomic changes and drug sensitivity patterns associated with the state of recurrence. Conclusions: Our results provide a transcriptional rationale for the lack of significant therapeutic benefit from temozolomide in patients with recurrent glioblastoma. Our findings imply that the spectrum of potentially effective drugs is likely to differ between newly diagnosed and recurrent glioblastomas and underscore the merits of glioblastoma stem cells as prognostic models for identifying alternative drugs and predicting drug response in recurrent glioblastoma. With the majority of recurrent glioblastomas being inoperable, glioblastoma stem cell models provide the means of compensating for the limited availability of recurrent glioblastoma specimens. MDPI 2020-02-24 /pmc/articles/PMC7072286/ /pubmed/32102350 http://dx.doi.org/10.3390/cancers12020520 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kim, Ella L.
Sorokin, Maxim
Kantelhardt, Sven Rainer
Kalasauskas, Darius
Sprang, Bettina
Fauss, Julian
Ringel, Florian
Garazha, Andrew
Albert, Eugene
Gaifullin, Nurshat
Hartmann, Christian
Naumann, Nicole
Bikar, Sven-Ernö
Giese, Alf
Buzdin, Anton
Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma
title Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma
title_full Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma
title_fullStr Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma
title_full_unstemmed Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma
title_short Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma
title_sort intratumoral heterogeneity and longitudinal changes in gene expression predict differential drug sensitivity in newly diagnosed and recurrent glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072286/
https://www.ncbi.nlm.nih.gov/pubmed/32102350
http://dx.doi.org/10.3390/cancers12020520
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