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Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer

The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.g., histone deacetylase inhibitors, HDACi) on gastric cancer (GC) remain elusive and recent studies suggested that the tumor microenvironment could contribute to the resistance. H...

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Autores principales: Venkatasamy, Aina, Guerin, Eric, Blanchet, Anais, Orvain, Christophe, Devignot, Véronique, Jung, Matthieu, Jung, Alain C., Chenard, Marie-Pierre, Romain, Benoit, Gaiddon, Christian, Mellitzer, Georg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467189/
https://www.ncbi.nlm.nih.gov/pubmed/34575561
http://dx.doi.org/10.3390/pharmaceutics13091485
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author Venkatasamy, Aina
Guerin, Eric
Blanchet, Anais
Orvain, Christophe
Devignot, Véronique
Jung, Matthieu
Jung, Alain C.
Chenard, Marie-Pierre
Romain, Benoit
Gaiddon, Christian
Mellitzer, Georg
author_facet Venkatasamy, Aina
Guerin, Eric
Blanchet, Anais
Orvain, Christophe
Devignot, Véronique
Jung, Matthieu
Jung, Alain C.
Chenard, Marie-Pierre
Romain, Benoit
Gaiddon, Christian
Mellitzer, Georg
author_sort Venkatasamy, Aina
collection PubMed
description The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.g., histone deacetylase inhibitors, HDACi) on gastric cancer (GC) remain elusive and recent studies suggested that the tumor microenvironment could contribute to the resistance. Hence, our objective was to gain information on the impact of cisplatin and the pan-HDACi SAHA (suberanilohydroxamic acid) on the tumor substructure and microenvironment of GC, by establishing patient-derived xenografts of GC and a combination of ultrasound, immunohistochemistry, and transcriptomics to analyze. The tumors responded partially to SAHA and cisplatin. An ultrasound gave more accurate tumor measures than a caliper. Importantly, an ultrasound allowed a noninvasive real-time access to the tumor substructure, showing differences between cisplatin and SAHA. These differences were confirmed by immunohistochemistry and transcriptomic analyses of the tumor microenvironment, identifying specific cell type signatures and transcription factor activation. For instance, cisplatin induced an “epithelial cell like” signature while SAHA favored a “mesenchymal cell like” one. Altogether, an ultrasound allowed a precise follow-up of the tumor progression while enabling a noninvasive real-time access to the tumor substructure. Combined with transcriptomics, our results underline the different intra-tumoral structural changes caused by both drugs that impact differently on the tumor microenvironment.
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spelling pubmed-84671892021-09-27 Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer Venkatasamy, Aina Guerin, Eric Blanchet, Anais Orvain, Christophe Devignot, Véronique Jung, Matthieu Jung, Alain C. Chenard, Marie-Pierre Romain, Benoit Gaiddon, Christian Mellitzer, Georg Pharmaceutics Article The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.g., histone deacetylase inhibitors, HDACi) on gastric cancer (GC) remain elusive and recent studies suggested that the tumor microenvironment could contribute to the resistance. Hence, our objective was to gain information on the impact of cisplatin and the pan-HDACi SAHA (suberanilohydroxamic acid) on the tumor substructure and microenvironment of GC, by establishing patient-derived xenografts of GC and a combination of ultrasound, immunohistochemistry, and transcriptomics to analyze. The tumors responded partially to SAHA and cisplatin. An ultrasound gave more accurate tumor measures than a caliper. Importantly, an ultrasound allowed a noninvasive real-time access to the tumor substructure, showing differences between cisplatin and SAHA. These differences were confirmed by immunohistochemistry and transcriptomic analyses of the tumor microenvironment, identifying specific cell type signatures and transcription factor activation. For instance, cisplatin induced an “epithelial cell like” signature while SAHA favored a “mesenchymal cell like” one. Altogether, an ultrasound allowed a precise follow-up of the tumor progression while enabling a noninvasive real-time access to the tumor substructure. Combined with transcriptomics, our results underline the different intra-tumoral structural changes caused by both drugs that impact differently on the tumor microenvironment. MDPI 2021-09-16 /pmc/articles/PMC8467189/ /pubmed/34575561 http://dx.doi.org/10.3390/pharmaceutics13091485 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Venkatasamy, Aina
Guerin, Eric
Blanchet, Anais
Orvain, Christophe
Devignot, Véronique
Jung, Matthieu
Jung, Alain C.
Chenard, Marie-Pierre
Romain, Benoit
Gaiddon, Christian
Mellitzer, Georg
Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer
title Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer
title_full Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer
title_fullStr Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer
title_full_unstemmed Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer
title_short Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer
title_sort ultrasound and transcriptomics identify a differential impact of cisplatin and histone deacetylation on tumor structure and microenvironment in a patient-derived in vivo model of gastric cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467189/
https://www.ncbi.nlm.nih.gov/pubmed/34575561
http://dx.doi.org/10.3390/pharmaceutics13091485
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