Biology subjects

Sastre-Perona, A.

Publications and source records attributed to Sastre-Perona, A..

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↗

bioRxiv2026

Overcoming Cisplatin Resistance in 3D Oral Squamous Cell Carcinoma Models via Nanoparticle-Mediated Pt(IV) Drug Delivery.

Advanced oral squamous cell carcinoma (OSCC) patients with cisplatin-refractory tumors face a poor prognosis and limited therapeutic options. Cisplatin-based systemic chemotherapy has long been the gold standard despite producing unmanageable adverse side effects and toxicity. Compared to Pt(II)-based analogs, octahedral Pt(IV)-based compounds have demonstrated remarkable potential as antitumor prodrugs. Pt(VI) derivates are chemically inert remaining intact until internalized within cells, demonstrating higher tolerability and selectivity towards cancer cells. In this study we compare antitumoral response implementing primary patient-derived 2D and 3D OSCC in vitro models treated with both cisplatin and a novel Pt(IV) compound. We also test the delivery and efficacy of these anticancer drugs via novel encapsulation of this Pt(IV) prodrug in the framework of mesoporous silica nanoparticles (Pt(IV)-cov@MSN). Our results show a significant improvement of delivery and cytotoxicity of Pt(IV)-cov@MSN in both cisplatin-responsive and cisplatin-resistant primary patient-derived in vitro models. We also show how Pt(IV)-cov@MSN elicits p53-dependent apoptotic cell death superior to that obtained with cisplatin treatment in OSCCs. These findings highlight 3D-primary models as key tools for drug and nanocarrier testing, as well as potential targeted and selective delivery strategies for novel chemotherapeutic agents.

cancer biology↗

bioRxiv2021

SOX2-phosphorylation toggles a bistable differentiation-switch in squamous cell carcinoma

The fate choice between stem cell self-renewal and differentiation is regulated by bistable transcriptional networks, which are balanced in homeostasis and imbalanced in tumors. Yet, how stem cells switch from self-renewal to differentiation remains a conundrum. Here, we discover a molecular mechanism that allows stem cell-like tumor propagating cells (TPCs) in squamous cell carcinomas (SCCs) to switch from a mutually exclusive SOX2-PITX1-TP63 self-renewal circuit to a KLF4 driven differentiation program, dependent on the relative occupancy of a novel Klf4-regulatory enhancer cluster (Klf4EC944) by SOX2 or KLF4, respectively. We find SOX2 occupies this site in TPCs to inhibit Klf4 transcription, but upon phosphorylation SOX2 becomes evicted from Klf4EC944, allowing residual KLF4 to occupy this site instead, boost the expression of KLF4 and its downstream targets, and differentiate self-renewing TPCs into post-mitotic SCC cells. This mechanism allows SOX2 to promote self-renewal and tumor formation, while preserving the differentiation potential in SCC cells. Our data suggest that stochastic cell fate decisions depend on the effective concentration of enzymatically regulated transcription factors. The surprising specificity by which SOX2-phosphorylation governs the bistable Klf4EC944 network-switch in SCCs reveals a conceptual framework for the identification of similar switches in other stem cell and cancer types and their potential development into cell type specific differentiation therapies for diseases in which tissue homeostasis has gone awry.

cancer biology↗

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↗