Dataset Information

Multi-omic analysis of Esophageal Adenocarcinoma uncovers candidate therapeutic targets and cancer-selective post-transcriptional regulation

ABSTRACT: Efforts to address the poor prognosis associated with esophageal adenocarcinoma (EAC) have been hampered by a lack of biomarkers to identify early disease and therapeutic targets. Despite extensive efforts to understand the somatic mutations associated with EAC over the past decade, a gap remains in understanding how the atlas of genomic aberrations in this cancer impacts the proteome and which somatic variants are of importance for the disease phenotype. We performed a quantitative proteomic analysis of 23 EACs and matched adjacent normal esophageal and gastric tissues. We explored the correlation of transcript and protein abundance using tissue-matched RNAseq and proteomic data from 7 patients and further integrated these data with a cohort of EAC RNA-seq data (n=264 patients), EAC whole-genome sequencing (n=454 patients) and external published datasets.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Esophagus Squamous Epithelium, Esophagus

DISEASE(S): Gastroesophageal Adenocarcinoma

SUBMITTER: Javier Alfaro

LAB HEAD: Javier Alfaro

PROVIDER: PXD042792 | Pride | 2024-08-10

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	2013_03_25_CAP_OT_61_HUP_PA60_F1.mzML	Mzml
	2013_03_25_CAP_OT_61_HUP_PA60_F1.mzid.gz	Mzid
	2013_03_25_CAP_OT_61_HUP_PA60_F1.raw	Raw
	2013_03_25_CAP_OT_62_HUP_PA60_F2.mzML	Mzml
	2013_03_25_CAP_OT_62_HUP_PA60_F2.mzid.gz	Mzid

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Publications

Multi-Omic Analysis of Esophageal Adenocarcinoma Uncovers Candidate Therapeutic Targets and Cancer-Selective Posttranscriptional Regulation.

O'Neill J Robert JR Yébenes Mayordomo Marcos M Mitulović Goran G Al Shboul Sofian S Bedran Georges G Faktor Jakub J Hernychova Lenka L Uhrik Lukas L Gómez-Herranz Maria M Kocikowski Mikołaj M Save Vicki V Vojtěšek Bořivoj B Arends Mark J MJ Hupp Ted T Alfaro Javier Antonio JA

Molecular & cellular proteomics : MCP 20240409 6

Efforts to address the poor prognosis associated with esophageal adenocarcinoma (EAC) have been hampered by a lack of biomarkers to identify early disease and therapeutic targets. Despite extensive efforts to understand the somatic mutations associated with EAC over the past decade, a gap remains in understanding how the atlas of genomic aberrations in this cancer impacts the proteome and which somatic variants are of importance for the disease phenotype. We performed a quantitative proteomic an ...[more]

PMID: 38604503

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Project description:Esophageal cancers (ECs) are highly aggressive tumors with poor prognosis and few treatment options. This study investigated the possibility of treating esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells by inhibitors of broad and specific histone deacetylases (HDACi; SAHA, MS-275, FK228) and/or of DNMT (Azacytidine, AZA). Drug targets (HDAC1,2,3 and DNMT1) were present in non-neoplastic (HET-1A), ESCC (OE21) and EAC (OE33) cell lines. All cell lines responded to HDACi by reduced HDAC activity and increased histone acetylation as well as to AZA by up-regulation of p21. Expression of drug targets remained largely unaffected by HDACi and AZA treatment. Importantly, cell viability, apoptosis, cell cycle dynamics and DNA damage were only affected by HDACi and/or AZA in ESCC and EAC, but not the non-neoplastic cells. This was specifically seen for the combination of MS-275 and AZA, leading to enhanced cancer cell selectivity and drug efficiency. By transcriptome analyses of MS-275, AZA and MS-275/AZA treated cells, known (e.g. p21) as well as novel regulated genes significantly associated with the cellular effects post HDACi and/or AZA treatment in ESCC and EAC cells were identified. Finally, human EC tissue specimens frequently expressed the actionable drug targets HDAC1/2/3 and DNMT1. In summary, a combined HDACi (MS-275)/AZA treatment is cancer cell selective and efficient in vitro. Since the majority of ECs express the drug targets in situ, this paves the way for further investigations of HDACi/AZA treatment in esophageal cancer cells and their translation into a clinico-pathological setting. To elucidate the transcriptome response to HDAC inhibitors of normal esophageal cells and esophageal tumor cells, total RNA was isolated from non-neoplastic esophageal epithelial cells (Het1A cells) a well as from two esophageal tumor cell lines (OE21 and OE33), respectively. Cells were treated with either MS-275, Azacytidine (AZA) or in combination of both. DMSO treatment was used as control in each case. Total RNA was isolated from cells 24 h after treatment and experiments were performed in biological triplicates.