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MDM2-amplified esophageal adenocarcinomas exhibit an activated metabolic and immunosuppressive phenotype with multiple potential therapeutic targets

ABSTRACT: A complete response following neoadjuvant therapy occurs only in a fraction of patients with esophageal adenocarcinoma (EAC). Further targeted treatment options are needed to improve treatment response and patient survival. Mouse double minute 2 homolog (MDM2) is a known oncogene. Its upregulation results in a more aggressive cancer phenotype. It is currently under investigation as a potential therapeutic target. However, initial findings have not been groundbreaking. Therefore, this study aimed to identify further potential therapeutic targets in the subtype of MDM2-amplified EAC.Methods: We screened 656 patients with operable esophageal adenocarcinoma for their MDM2-amplification status using Fluorescence in situ Hybridization (FISH). 57 tumors (8.7%) were MDM2-amplified. The proteome of 35 MDM2-amplified and 37 non-amplified tumors was analyzed using mass spectrometry. 22.2% of the included patients were primarily resected, and 77.8% were neoadjuvant treated.Results: The comparison of MDM2-amplified and non-amplified tumors revealed various differently expressed proteins and pathways. Hornerin, Bystin, and subtypes of keratins (KRT1, KRT2, KRT9, KRT10) were significantly downregulated. Whereas Choline transporter-like protein 2 (CTL2), Cullin-associated NEDD8-dissociated protein 1 (CAND1), FAD- and RhoGTPase-binding protein 1 (FARP1), and Contactin 1 were upregulated in MDM2-amplified EAC. Enrichment analyses revealed that MDM2-amplified esophageal adenocarcinomas showed a more pronounced immunosuppressive phenotype due to the downregulation of interferon signaling pathways and antigen presentation. Furthermore, distinct metabolic pathways like carbon, propanoate, tryptophan, and tyrosine metabolism were upregulated in MDM2-amplified tumors.Conclusion:In this study, we investigated the whole proteome of MDM2-amplified compared to non-amplified esophageal adenocarcinomas. We described numerous potential future therapeutic targets, suggesting patients with MDM2-amplified tumors could potentially benefit from, exemplary, Mitogen-activated protein kinase kinase (MEK) inhibitors or tryptophan metabolism inhibitors. Future mechanistic studies are needed to validate these findings.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Esophageal Adenocarcinoma Cell

DISEASE(S): Esophagus Adenocarcinoma

SUBMITTER: Proteomics Facility

LAB HEAD: Alexander Quaas

PROVIDER: PXD058762 | Pride | 2025-12-15

REPOSITORIES: Pride

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MDM2-amplified esophageal adenocarcinomas exhibit an activated metabolic and immunosuppressive phenotype with multiple potential therapeutic targets.

Knipper Karl K Bruns Christiane J CJ Popp Felix C FC Schmidt Thomas T Grothey Bastian B Quaas Alexander A Lyu Su Ir SI

BMC cancer 20251126 1

PMID: 41299419

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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.

Project description:We applied whole-genome single nucleotide polymorphism (SNP) arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range 23-208) per tumor. LOH and gains averaged 33 (range 3-83) and 31 (range 11-73) per tumor, respectively. Copy neutral LOH events averaged 27 (range 7-57) per EAC. We noted 126 homozygous deletions (HDs) across the EAC panel (range 0-11 in individual tumors). Frequent HDs within FHIT (17/23), WWOX (8/23) and DMD (6/23) suggest a role for common fragile sites or genomic instability in EAC etiology. HDs were also noted for known tumor suppressor genes (TSGs) including: CDKN2A, CDKN2B, SMAD4 and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs. All tumors showed LOH for most of chromosome 17p, suggesting that TSGs other than TP53 maybe targeted. Frequent gains were noted around MYC (13/23), BCL9 (12/23), CTAGE1 (14/23) and ZNF217 (12/23). Thus, we have confirmed previous reports indicating frequent changes to FHIT, CDKN2A, TP53 and MYC in EAC and identified additional genes of interest. Meta analysis of previous genome-wide EAC studies together with the data presented here, highlighted consistent regions of gain on 8q, 18q and 20q, and multiple LOH regions on 4q, 5q, 17p and 18q, suggesting that more than one gene may be targeted on each of these chromosome arms. The focal gains and deletions documented here are a step towards identifying the key genes involved in EAC development. Keywords: High Density SNP array Here we use Illumina 317K whole-genome single-nucleotide polymorphism arrays to define a comprehensive allelotype of melanoma based on loss of heterozygosity (LOH) and copy number changes in a panel of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies. Each EAC was paired to normal squamous biopsy from 40328 (GSM266078) to generate the log_R_ratio.

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