Biology subjects

Montuenga, L. M.

Publications and source records attributed to Montuenga, L. M..

5 recordsLinked to original sources

bioRxiv2026

RNA and protein are not interchangeable in single-cell spatial multi-omics

Spatial transcriptomics is increasingly used to infer cellular phenotypes, molecular interactions, and functional tissue organization from RNA, although most of these biological processes are ultimately mediated by proteins. Here, we directly tested the interchangeability of spatial RNA and protein measurements using paired Xenium profiling of 21 matched targets across ~1.8 million cells from primary lung adenocarcinoma and metastatic castration-resistant prostate cancer. After accounting for marker- and dataset-specific protein background, we quantified concordance at multiple levels, including single-cell detection, expression magnitude, cell-type distribution, patient-level abundance, and spatial organization. Agreement at single-cell level was strongly marker-dependent. Canonical lineage markers generally showed concordant RNA and protein patterns, whereas several molecules, including in our study PD-1, PD-L1, and LAG-3, showed little concordance across modalities. Importantly, spatial organization remained substantially more discordant between modalities than overall abundance, indicating that spatial biomarkers are not directly transferable across modalities. Together, our results show that spatial RNA and protein measurements provide largely overlapping information for lineage markers and overall abundance, but can diverse for specific molecules and for higher-order spatial features, where the two layers provide complementary rather than equivalent readouts. These findings provide practical guidance on when spatial transcriptomic readouts can be interpreted as proxies for protein and when orthogonal protein validation is advisable.

cancer biology↗

bioRxiv2025

FMO4 drives lung adenocarcinoma by stabilizing the MAT2A/MAT2B complex and hindering ferroptosis

Lung cancer is the leading cause of death by cancer in the world and finding new targets is a major medical need to tackle this disease. Here, upon proteomic analysis to identify common players in oncogenic EGFR- and KRAS-driven lung adenocarcinoma mouse models, we uncovered a largely unknown protein in cancer, flavin-containing monooxygenase 4 (FMO4), whose expression was increased in lung tumors compared with adjacent lung tissue. FMO4 expression was strongly increased also in lung cancer samples from patients compared with healthy lung, and its expression level was inversely correlated with overall survival. Remarkably, in vivo deletion of FMO4 greatly decreased tumor burden and increased survival in oncogenic KRAS-driven lung adenocarcinoma mice unveiling its crucial role in tumor biology. Mechanistically, we found that FMO4 loss of function promotes ferroptosis and cooperates with ferroptosis inducers in vitro and in vivo. Moreover, FMO4 facilitates the interaction between MAT2A and MAT2B, promoting the generation of cysteine from methionine, which in turn boosts the generation of glutathione, thus protecting lung adenocarcinoma against ferroptosis. In summary we identified a new target in lung adenocarcinoma with important implications in cancer biology.

cancer biology↗

bioRxiv2024

MDM2 stabilization of Notch intracellular domain upon DNA damage plays a major role in non-small cell lung carcinoma response to platinum chemotherapy

Despite major advances in lung cancer clinical management, majority of patients suffering non-small cell lung carcinoma (NSCLC) are treated in first line with platinum in combination with immune checkpoint inhibitors. Although platinum compounds normally display an initial therapeutic effect, relapse constitutes a major challenge in the clinical management of NSCLC patients. Therefore, it is fundamental to understand the relapse underlying mechanisms to find new therapeutic opportunities to improve patients survival. Here, we found that different DNA damage inducers increase the protein levels of Notch Intracellular Domain (NICD), i.e., the active form of NOTCH1. Mechanistically, we unveiled that upon platinum treatment, there was a concomitant increase of MDM2 together with NICD, and we also observed an MDM2-mediated ubiquitination and stabilization of NICD. Of note, using patient-derived xenografts displaying intrinsic carboplatin resistance, we demonstrated that the combination of carboplatin with MDM2 and NICD inhibitors increased survival and reduced tumor growth compared with carboplatin in monotherapy. Moreover, in patients with NSCLC who received platinum chemotherapy, MDM2 expression level in the tumor was correlated with poor progression-free survival, further validating MDM2 key role in the response to platinum compounds. Our findings open a therapeutic opportunity for NSCLC patients, the main lung cancer subtype of the leading cause of death by cancer worldwide.

cancer biology↗

bioRxiv2022

miRNome profiling of lung cancer metastases revealed a key role for miRNA-PD-L1 axis in the modulation of chemotherapy response

Locally-advanced non-small-cell lung cancer (NSCLC) is frequent at diagnosis and requires multimodal treatment approaches. Neoadjuvant chemotherapy (NACT) followed by surgery is the treatment of choice for operable locally-advanced NSCLC (Stage IIIA). However, the majority of patients are NACT-resistant and shows persistent lymph nodal metastases (LNmets) and an adverse outcome. Therefore, the identification of mechanisms and biomarkers of NACT resistance is paramount for ameliorating prognosis of patients with Stage IIIA NSCLC. Here, we investigated the miRNome and transcriptome of chemo naive LNmets collected from patients with Stage IIIA NSCLC (N=64). We found that a microRNA signature accurately predicts NACT response. Mechanistically, we discovered a miR-455-5p/PD-L1 regulatory axis which drives chemotherapy resistance, hallmarks metastases with active IFN-{gamma} response pathway (an inducer of PD-L1 expression), and impacts T cells viability and relative abundances in tumor-microenviroment (TME). Our data provides new biomarkers to predict NACT response and adds molecular insights relevant for improving the management of patients with locally-advanced NSCLC.

cancer biology↗

bioRxiv2017

Comparison of RNA-seq and Microarray Platforms for Splice Event Detection using a Cross-Platform Algorithm

RNA-seq is a reference technology for determining alternative splicing at genome-wide level. Exon arrays remain widely used for the analysis of gene expression, but show poor validation rate with regard to splicing events. Commercial arrays that include probes within exon junctions have been developed in order to overcome this problem.\n\nWe compare the performance of RNA-seq (Illumina HiSeq) and junction arrays (Affymetrix Human Transcriptome array) for the analysis of transcript splicing events. Three different breast cancer cell lines were treated with CX-4945, a drug that severely affects splicing. To enable a direct comparison of the two platforms, we adapted EventPointer, an algorithm that detects and labels alternative splicing events using junction arrays, to work also on RNA-seq data. Common results and discrepancies between the technologies were validated and/or resolved by over 200 PCR experiments.\n\nAs might be expected, RNA-seq appears superior in cases where the technologies disagree, and is able to discover novel splicing events beyond the limitations of physical probe-sets. We observe a high degree of coherence between the two technologies, however, with correlation of EventPointer results over 0.90. Through decimation, the detection power of the junction arrays is equivalent to RNA-seq with up to 60 million reads. Our results suggest, therefore, that exon-junction arrays are a viable alternative to RNA-seq for detection of alternative splicing events when focusing on well-described transcriptional regions.

bioinformatics↗