Biology subjects

Ibanez de Caceres, I.

Publications and source records attributed to Ibanez de Caceres, I..

4 recordsLinked to original sources

bioRxiv2026

Epigenetic silencing of MAFG is a potential prognosis biomarker in lung adenocarcinomas

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality, partly because it is often diagnosed at advanced stages and frequently develops resistance to platinum-based chemotherapy. We previously showed that MAFG becomes derepressed following miR-7 hypermethylation, promoting platinum resistance in NSCLC and ovarian cancer cell lines. Although MAFG is a well-established regulator of oxidative stress, recent evidence in melanoma and colorectal cancer suggests an additional role as a regulator of methylator phenotypes. However, how MAFG reshapes the lung cancer epigenome remains unknown. Here, we investigated the contribution of MAFG to DNA methylation remodeling by combining CRISPR/Cas9-mediated MAFG deletion with CpG-Methyl-Array profiling, followed by expression (qPCR) and methylation (qMSP) validation in tumor cell lines. Our translational approach integrated aptahistochemistry using MAFG-specific aptamers in 127 NSCLC patients, methylation analysis in 35 fresh-frozen tumors and 40 FFPE samples, and interrogation of TCGA methylation datasets. MAFG loss reduced promoter methylation of LIF and MAFG itself. Importantly, these effects were subtype-specific, with MAFG expression and methylation displaying distinct transcriptional programs in LUAD versus LUSC, and prognostic associations restricted to KRAS-mutated adenocarcinomas. In NSCL in silico and in house cohorts, lower MAFG methylation and higher MAFG protein levels were both associated with worse prognosis. In summary, our findings identify MAFG as a regulator of DNA methylation in NSCLC and support the use of MAFG DNA methylation, or protein levels as clinically relevant prognostic biomarkers, particularly in lung adenocarcinoma.

cancer biology↗

bioRxiv2024

Unveiling miR-451a and miR-142-3p as Prognostic Markers in NSCLC via sEV Liquid Biopsy

Despite advancements in personalized cancer therapies, platinum-based chemotherapy remains the cornerstone for treating solid tumors, including Non-Small Cell Lung Cancer (NSCLC). The integration of novel immunotherapies with platinum compounds has shown promising outcomes for the treatment of advanced disease. However, a significant proportion of patients experience therapeutic failure due to innate or acquired resistance. Thus, identifying molecular profiles and biomarkers to monitor patient progress and treatment response is crucial for tailoring therapeutic strategies. Small extracellular vesicle (sEV)-based liquid biopsy emerges as a promising non-invasive method for cancer management. sEVs play a critical role in cell communication and provide molecular insights into the tumor environment. In this study, we characterized the microRNome content of sEVs from cisplatin-resistant and -sensitive cancer cells using small-RNA sequencing. We identified and validated three miRNAs in two cohorts of 78 and 49 patients treated with either chemotherapy alone or chemo-immunotherapy, respectively, analyzed via liquid biopsy, differentiating NSCLC patients based on progression and overall survival. Notably, miR-451a emerged as a prognostic marker for chemo and chemo-immunotherapy, while miR-142-3p was identified for the first time as a potential prognostic marker specifically for stage IV patients, irrespective of the treatment. The combination of miR-451, miR-142-3p, and miR-55745, a novel miRNA identified from our miRNome screening, serves as a valuable biomarker for both cisplatin and chemo-immunotherapy treatment responses. This study underscores the role of sEVs in acquired cisplatin resistance and introduces novel miRNA-sEV biomarkers for managing NSCLC progression.

cancer biology↗

bioRxiv2020

The SEQC2 Epigenomics Quality Control (EpiQC) Study: Comprehensive Characterization of Epigenetic Methods, Reproducibility, and Quantification

Cytosine modifications in DNA such as 5-methylcytosine (5mC) underlie a broad range of developmental processes, maintain cellular lineage specification, and can define or stratify cancer and other diseases. However, the wide variety of approaches available to interrogate these modifications has created a need for harmonized materials, methods, and rigorous benchmarking to improve genome-wide methylome sequencing applications in clinical and basic research. Here, we present a multi-platform assessment and a global resource for epigenetics research from the FDAs Epigenomics Quality Control (EpiQC) Group. The study design leverages seven human cell lines that are designated as reference materials and publicly available from the National Institute of Standards and Technology (NIST) and Genome in a Bottle (GIAB) consortium. These samples were subject to a variety of genome-wide methylation interrogation approaches across six independent laboratories, with a primary focus was on 5-methylcytosine modifications. Each sample was processed in two or more technical replicates by three whole-genome bisulfite sequencing (WGBS) protocols (TruSeq DNA methylation, Accel-NGS MethylSeq, and SPLAT), oxidative bisulfite sequencing (TrueMethyl), one enzymatic deamination method (EMseq), targeted methylation sequencing (Illumina Methyl Capture EPIC), and single-molecule long-read nanopore sequencing from Oxford Nanopore Technologies. After rigorous quality assessment and comparison to Illumina EPIC methylation microarrays and testing on a range of algorithms (Bismark, BitmapperBS, BWAMeth, and GemBS), we found overall high concordance between assays (R=0.87-R0.93), differences in efficency of read mapping and CpG capture and coverage, and platform performance. The data provided herein can guide continued used of these reference materials in epigenomics assays, as well as provide best practices for epigenomics research and experimental design in future studies.

genomics↗

bioRxiv2019

A novel role for the tumor suppressor gene ITF2 in lung tumorigenesis through the action of Wnt signaling pathway

Despite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyze the cytogenetic alterations that arise after cisplatin treatment providing novel insights into the molecular biology and the cellular mechanisms involved in the acquired resistance in these tumor types. MethodsIn this study, we used 1 million array-CGH and qRT-PCR methodologies to identify and validate cytogenetic alterations that arise after cisplatin treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines. We used whole transcriptome sequencing (RNA-seq), functional transfection assays and gene-pathway activity analysis in our experimental cellular models and in fresh frozen primary NSCLC tumors to identify genes with a potential role in the development of this malignancy. Results were further explored in 55 lung and ovarian primary tumors and control samples and in two extensive in silico databases (TCGA and KMplotter) with 1,926 NSCLC and 1,425 additional epithelial tumors. ResultsLong-term cell exposure to platinum induces the frequent deletion of ITF2 gene. Restoration of ITF2 expression re-sensitizes tumor cells to platinum and recovers the levels of Wnt/{beta}-catenin transcriptional activity. ITF2 expression was also frequently downregulated in NSCLC, ovarian and other epithelial tumors, predicting a worse overall survival. We also identified an inverse correlation in expression between ITF2 and HOXD9, revealing that NSCLC patients with lower expression of HOXD9 have a better overall survival rate that was independent of the tumor histology. ConclusionWe have defined the implication of ITF2 as a molecular mechanism behind the development of cisplatin resistance probably through the activation of the Wnt-signaling pathway. Our translational data suggest that ITF2 could be used as a general epithelial tumor platinum-predictive marker and have identified HOXD9 as a potential prognostic biomarker in NSCLC, a gene which expression is induced by Wnt signaling. Furthermore, this data highlights the possible role of ITF2 and HOXD9 as a novel therapeutic target for platinum resistant tumors.

cancer biology↗