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

Pharmaceutics

Matthieu Jung¹  Marie-Pierre Chenard²  Alain C. Jung³  Christian Gaiddon³  Eric Guerin³  Christophe Orvain³  Véronique Devignot³  Georg Mellitzer³  Anais Blanchet³  Aina Venkatasamy³  Benoit Romain³ 

[1] IGBMC, GenomEast, 67400 Illkirch, France;Pathology Department, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France;Streinth Lab (Stress Response and Innovative Therapies), Strasbourg University, Inserm UMR_S 1113 IRFAC (Interface Recherche Fondamental et Appliquée à la Cancérologie), 67200 Strasbourg, France;

关键词: gastric cancer;    cisplatin;    ultrasound;    HDAC Inhibitors;    SAHA;    p53;   

DOI  :  10.3390/pharmaceutics13091485

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown