Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

URI permanent per a aquesta col·leccióhttps://hdl.handle.net/2445/98743

Estadístiques

Examinar

Mostrant 1 - 20 de 409

Nuclear stiffness through lamin A/C overexpression differentially modulates chromosomal instability biomarkers
(Wiley, 2025-02-25) Bosch Calvet, Mireia; Pérez Venteo, Alejandro; Cebria Xart, Alex; Garcia Cajide, Marta; Mauvezin, Caroline
Background Information Mitosis is crucial for the faithful transmission of genetic material, and disruptions can result in chromosomal instability (CIN), a hallmark of cancer. CIN is a known driver of tumor heterogeneity and anti-cancer drug resistance, thus highlighting the need to assess CIN levels in cancer cells to design effective targeted therapy. While micronuclei are widely recognized as CIN markers, we have recently identified the toroidal nucleus, a novel ring-shaped nuclear phenotype arising as well from chromosome mis-segregation. Results Here, we examined whether increasing nuclear envelope stiffness through lamin A/C overexpression could affect the formation of toroidal nuclei and micronuclei. Interestingly, lamin A/C overexpression led to an increase in toroidal nuclei while reducing micronuclei prevalence. We demonstrated that chromatin compaction and nuclear stiffness drive the formation of toroidal nuclei. Furthermore, inhibition of autophagy and lysosomal function elevated the frequency of toroidal nuclei without affecting the number of micronuclei in the whole cell population. We demonstrated that this divergence between the two CIN biomarkers is independent of defects in lamin A processing. Conclusions and Significance These findings uncover a complex interplay between nuclear architecture and levels of CIN, advancing our understanding of the mechanisms supporting genomic stability and further contributing to cancer biology.
Harnessing dendritic cell metabolism for healthy ageing: reducing the risk of cardiovascular disease?
(2024-06-06) Wculek, Stefanie Kristin
Success and Limitations of Current Force Fields for the Description of RNA–Ligand Complexes
(American Chemical Society, 2025-10-31) Fernández Migens, Paula; Serrano Chacón, Israel; Orozco López, Modesto; Battistini, Federica
We present a systematic assessment of the last generation of RNA force fields to reproduce the structures and dynamics of ligand−RNA complexes. Our comprehensive analysis helped not only to define the more reliable force field to represent complex structures but also suggests details that can be improved and provide a critical analysis of the quality of experimental structures in complex systems that are expected to be very flexible and environment dependent.
The DNA dialect: a comprehensive guide to pretrained genomic language models
(EMBO Press en asociación con Springer Nature, 2026-01-19) Veiner, Marcell; Supek, Fran
Following their success in natural language processing and protein biology, pretrained large language models have started appearing in genomics in large numbers. These genomic language models (gLMs), trained on diverse DNA and RNA sequences, promise improved performance on a variety of downstream prediction and understanding tasks. In this review, we trace the rapid evolution of gLMs, analyze current trends, and offer an overview of their application in genomic research. We investigate each gLM component in detail, from training data curation to the architecture, and highlight the present trends of increasing model complexity. We review major benchmarking efforts, suggesting that no single model dominates, and that task-specific design and pretraining data often outweigh general model scale or architecture. In addition, we discuss requirements for making gLMs practically useful for genomic research. While several applications, ranging from genome annotation to DNA sequence generation, showcase the potential of gLMs, their use highlights gaps and pitfalls that remain unresolved. This guide aims to equip researchers with a grounded understanding of gLM capabilities, limitations, and best practices for their effective use in genomics.
Joint inference of mutational signatures from indels and single-nucleotide substitutions reveals prognostic impact of DNA repair deficiencies
(BMC, 2025-07-03) Ferrer Torres, Patricia; Galvan Femenia, Ivan ; Supek, Fran
BackgroundMutational signatures are increasingly used to understand the mechanisms causing cancer. However, their important applications in predicting prognosis and stratifying patients for therapy are hampered by inaccurate inference of the various featureless, dense trinucleotide mutational spectra, which are often confounded with one another. One of them is the homologous recombination deficiency (HRd)-associated signature SBS3, relevant because of its association with prognosis in ovarian and breast cancer and because of its potential as a biomarker for synthetic lethality therapies.MethodsHere, we highlight strong benefits of a multimodal approach for mutational signature extraction, applied on top of standard bioinformatic pipelines. By jointly operating on single-base substitution (SBS) and indel (ID) spectra, this method enables accurate identification of various DNA repair deficiency signatures and patient survival prediction.ResultsAcross four different cohorts of whole-genome sequenced high-grade serous ovarian cancers (HGSOC), the multimodal SBS + ID approach correctly distinguished the commonly confused signatures SBS3, SBS5, SBS8, SBS39, and SBS40. Importantly, we robustly identified two different multimodal SBS3 signatures, m-SBS3a and m-SBS3b, with distinct patterns in the indel spectrum. Multimodal SBS3b signature was strongly predictive of longer survival in ovarian cancer patients, replicating across four cohorts, with effect sizes greatly exceeding other genetic markers. Our m-SBS3 also predicted survival in platinum-treated patients with various cancer types, and moreover, the SBS + ID joint inference was successfully applied to mismatch repair-deficient colorectal cancer and immunotherapy response, supporting a general utility of the multimodal mutational signatures approach.ConclusionsOverall, combining SBS and ID mutations improves detection of HR deficiency-associated signatures and reveals distinct SBS3 subtypes with prognostic value. This multimodal approach outperforms existing markers and is readily applicable to therapy stratification.
DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy
(Nature Communications, 2025-05-13) Khalil, Ahmed; Supek, Fran
Somatic cells can transform into tumors due to mutations, and the tumors further evolve towards increased aggressiveness and therapy resistance. We develop DiffInvex, a framework for identifying changes in selection acting on individual genes in somatic genomes, drawing on an empirical mutation rate baseline derived from non-coding DNA that accounts for shifts in neutral mutagenesis during cancer evolution. We apply DiffInvex to >11,000 somatic whole-genome sequences from similar to 30 cancer types or healthy tissues, identifying genes where point mutations are under conditional positive or negative selection during exposure to specific chemotherapeutics, suggesting drug resistance mechanisms occurring via point mutation. DiffInvex identifies 11 genes exhibiting treatment-associated selection for different classes of chemotherapies, linking selected mutations in PIK3CA, APC, MAP2K4, SMAD4, STK11 and MAP3K1 with drug exposure. Various gene-chemotherapy associations are further supported by differential functional impact of mutations pre- versus post-therapy, and are also replicated in independent studies. In addition to nominating drug resistance genes, we contrast the genomes of healthy versus cancerous cells of matched human tissues. We identify noncancerous expansion-specific drivers, including NOTCH1 and ARID1A. DiffInvex can also be applied to diverse analyses in cancer evolution to identify changes in driver gene repertoires across time or space.
Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations
(Nature Communications, 2024-07-20) Besedina, Elizaveta; Supek, Fran
Cancer driver genes can undergo positive selection for various types of genetic alterations, including gain-of-function or loss-of-function mutations and copy number alterations (CNA). We investigated the landscape of different types of alterations affecting driver genes in 17,644 cancer exomes and genomes. We find that oncogenes may simultaneously exhibit signatures of positive selection and also negative selection in different gene segments, suggesting a method to identify additional tumor types where an oncogene is a driver or a vulnerability. Next, we characterize the landscape of CNA-dependent selection effects, revealing a general trend of increased positive selection on oncogene mutations not only upon CNA gains but also upon CNA deletions. Similarly, we observe a positive interaction between mutations and CNA gains in tumor suppressor genes. Thus, two-hit events involving point mutations and CNA are universally observed regardless of the type of CNA and may signal new therapeutic opportunities. An analysis with focus on the somatic CNA two-hit events can help identify additional driver genes relevant to a tumor type. By a global inference of point mutation and CNA selection signatures and interactions thereof across genes and tissues, we identify 9 evolutionary archetypes of driver genes, representing different mechanisms of (in)activation by genetic alterations.
Variable efficiency of nonsense-mediated mRNA decay across human tissues, tumors and individuals
(BMC, 2025-09-29) Palou Márquez, Guillermo; Supek, Fran
BackgroundNonsense-mediated mRNA decay (NMD) is a quality-control pathway that degrades mRNA bearing premature termination codons (PTCs) resulting from mutation or mis-splicing, and that additionally participates in gene regulation of unmutated transcripts. While NMD activity is known to differ between examples of PTCs, it is less well studied if human tissues differ in NMD activity, or if individuals differ.ResultsWe analyzed exomes and matched transcriptomes from Human tumors and healthy tissues to quantify individual-level NMD efficiency, and assess its variability between tissues, tumors, and individuals. This was done by monitoring mRNA levels of endogenous NMD target transcripts, and additionally supported by allele-specific expression of germline PTCs. Nervous system and reproductive system tissues have lower NMD efficiency than other tissues, such as the digestive tract. Next, there is systematic inter-individual variability in NMD efficiency, and we identify two underlying mechanisms. First, somatic copy number alterations can robustly associate with NMD efficiency, prominently the commonly-occurring gain at chromosome 1q that encompasses two core NMD genes: SMG5 and SMG7 and additional functionally interacting genes such as PMF1 and GON4L. Second, deleterious germline variants in genes such as the KDM6B chromatin modifier can associate with higher or lower NMD efficiency in individuals. Variable NMD efficiency modulates positive selection upon somatic nonsense mutations in tumor suppressor genes, and is associated with cancer patient survival and immunotherapy responses. ConclusionsNMD efficiency is variable across human tissues, and it is additionally variable across individuals and tumors thereof due to germline and somatic genetic alterations.
Editorial: The impact of lipid metabolism on cancer progression and metastasis
(Frontiers Media, 2025-12-10) Aydemir, Duygu; Martín Pérez, Miguel; Sunami, Yoshiaki
Recent advances in oncology, immunology, and metabolic medicine have increasingly positioned lipid metabolism as a central determinant of cancer initiation, progression, and therapeutic response. Across multiple domains, lipid metabolic pathways are now understood to intersect with endocrine regulation, immune cell function, and systemic metabolic homeostasis, thereby influencing tumor behavior at both cellular and organismal levels. This expanding body of evidence highlights lipid metabolism not as an isolated biochemical process, but as an integrative axis that coordinates metabolic, immunological, and endocrine signals within the tumor microenvironment and throughout the host. Such a multidimensional perspective underscores the importance of synthesizing cross-disciplinary findings to fully elucidate the mechanistic and translational relevance of lipid metabolic regulation in contemporary cancer research.
Effects of removable clear dental aligners on the composition of the oral microbiome
(2025-12-31) Peregrina Cabredo, Sara; Peiró Aubalat, Andrea; Manohar, Avié; Benavente, Alicia; Torres Carvajal, Martha; Gabaldón Esteban, Toni
Proper tooth alignment is important for oral and periodontal health, allowing better hygiene and reducing plaque build-up. While traditional braces are effective, clear aligners offer an aesthetic advantage and are also thought to promote better oral hygiene. However, their specific impact on the oral microbiome is not yet fully understood. This longitudinal study used 16S amplicon sequencing to study the oral microbiome (from saliva, subgingival, and supragingival samples) of 11 patients undergoing clear aligner treatment. Samples were collected at three time points: before treatment and at 3 and 6 months during therapy. Our results revealed large differences between the microbiomes of different oral sites but no significant overall changes in the oral microbiome composition due to orthodontic treatment. While some species-specific changes were observed, their effect sizes were very small. Although these results should be confirmed in a larger and more diverse cohort, they suggest that the treatment had a small or negligible impact. Given the observed stability of the oral microbiome in all three studied niches throughout the treatment and the known benefits to oral hygiene, clear aligners may present a favorable therapeutic alternative compared to fixed appliances.
Molecular simulations meet personalized medicine: The mechanism of action of CLC-5 antiporter and the origin of Dent's disease
(2025-11-01) Macaluso, Veronica; Pérez, Carles; Soliva, Robert; Westermaier, Yvonne; Díaz, Lucía; Wieczór, Milosz ; Orozco López, Modesto
ClC-5 is a Cl-/H+ antiporter crucial for the homeostasis of the entire organism, and whose functional deficiencies cause pathologies such as Dent's disease, a rare genetic disorder that can have lethal consequences. While the clinical aspects of the pathology are known, its molecular basis is elusive, which hampers the development of potential therapies. We present here a systematic study, where we explore the mechanism of transport of ClC-5, deciphering the choreography of structural changes required for the transport of chloride ions and protons in opposing directions. Once the mechanism is determined, we explore how the 523 Delta Val deletion linked to Dent's disease hampers the correct functioning of the transporter, despite having a very minor structural impact. Our study highlights how state-of-the-art simulation methods can shed light on the origin of rare diseases and explore targets for personalized medicine.
Phylogeny-aware Simulations Suggest a Low Impact of Unsampled Lineages in the Inference of Gene Flow During Eukaryogenesis
(2025-11-01) Bernabeu, Moises; Manzano Morales, Saioa ; Gabaldón Esteban, Toni
The topologies of gene trees are broadly used to infer horizontal gene transfer events and characterize the potential donor and acceptor partners. Additionally, ratios between branch lengths in the gene tree can inform about the timing of transfers relative to each other. Using this approach, recent studies have proposed a relative chronology of gene acquisitions in the lineage leading to the last eukaryotic common ancestor. However, a recognized caveat of the branch-length ratio method are potential biases due to incomplete taxon sampling resulting in so-called "ghost" lineages. Here, we assessed the effect of ghost lineages on the inference of the relative ordering of gene acquisition events during eukaryogenesis. For this, we used a novel simulation framework that populates a dated Tree of Life with plausible "ghost" lineages and simulates their gene transfers to the lineage leading to last eukaryotic common ancestor. Our simulations suggest that a substantial majority of gene acquisitions from distinct ghost donors are inferred with the correct relative order. However, we identify phylogenetic placements where ghost lineages would be more likely to produce misleading results. Overall, our approach offers valuable guidance for the interpretation of future work on eukaryogenesis, and can be readily adapted to other evolutionary scenarios.
Cytoplasmic Regulation of the Poly(A) Tail Length as a Potential Therapeutic Target
(2025-01-13) Fernandez, Mercedes; Méndez De La Iglesia, Raúl
Mendez, Raul
Sex and smoking bias in the selection of somatic mutations in human bladder
(Springer Nature, 2025-10-08) Calvet, Ferriol; Blanco Martínez Illescas, Raquel; Muiños Ballester, Ferran; Tretiakova, Maria; Latorre Esteves, Elena S.; Fredrickson, Jeanne; Andrianova, Maria; Pellegrini, Stefano; Rosendahl Huber, Axel; Ramis Zaldívar, Joan Enric; An, Shuyi Charlotte; Thieme, Elana; Kohrn, Brendan F.; Grau, Miguel L.; González Pérez, Abel; López Bigas, Núria; Risques, Rosa Ana
Men are at higher risk of several cancer types than women1. For bladder cancer the risk is four times higher for reasons that are not clear2. Smoking is also a principal risk factor for several tumour types, including bladder cancer3. As tumourigenesis is driven by somatic mutations, we wondered whether the landscape of clones in the normal bladder differs by sex and smoking history. Using ultradeep duplex DNA sequencing (approximately 5,000x), we identified thousands of clonal driver mutations in 16 genes across 79 normal bladder samples from 45 people. Men had significantly more truncating driver mutations in RBM10, CDKN1A and ARID1A than women, despite similar levels of non-protein-affecting mutations. This result indicates stronger positive selection on driver truncating mutations in these genes in the male urothelium. We also found activating TERT promoter mutations driving clonal expansions in the normal bladder that were associated strongly with age and smoking. These findings indicate that bladder cancer risk factors, such as sex and smoking, shape the clonal landscape of the normal urothelium. The high number of mutations identified by this approach offers a new strategy to study the functional effect of thousands of mutations in vivo-natural saturation mutagenesis-that can be extended to other human tissues.
Clonal tracing with somatic epimutations reveals dynamics of blood ageing
(Springer Nature, 2025-05-21) Scherer, Michael; Singh, Indranil; Braun, Martina Maria; Szu Tu, Chelsea; Sánchez Sánchez, Pedro; Lindenhofer, Dominik; Jakobsen, Niels Asger; Körber,Verena; Kardorff, Michael; Nitsch, Lena; Kautz, Pauline; Rühle, Julia; Bianch, Agostina; Cozzuto, Luca; Frömel, Robert; Beneyto Calabuig, Sergi; Lareau, Caleb; Satpathy, Ansuman T.; Beekman, Renée; Steinmetz, Lars M.; Raffel, Simon; Ludwig, Leif S.; Vyas, Paresh; Rodríguez Fraticelli, Alejo E.; Velten, Lars
Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.
Mutations that stick: Unexpected discovery of molecular glue mimicry
(Elsevier, 2025-04-17) Whelan, Rory; José Durán, Ferran; Mayor Ruiz, Cristina
Opportunities in proximity modulation: Bridging academia and industry
(Elsevier, 2025-08-21) Mayor-Ruiz, Cristina; Winter, Georg E.; Koch, Kerstin; Ciulli, Alessio; Thomä, Nicolas H.; Dikic, Ivan
In the past decade, exciting therapeutic strategies to harness the ubiquitin-proteasome system (UPS) for degradation of target proteins have emerged. Proximity-inducing modalities are at the center of these strategies and act by modulating protein-protein interactions. While we are still learning to harvest this approach, it holds tremendous promise for developing treatments for hitherto undruggable proteins. Here, we discuss how academic efforts and academic-industrial collaboration have advanced the development of therapeutic modalities based on the principle of roximity induction. We make a case for forming a global academia-industry alliance to enhance access to training and expertise while accelerating innovation and translation from ground-breaking ideas to proof of concept in the clinic.
Dysregulation of the FGF21-adiponectin axis in a large cohort of patients with severe obesity and liver disease
(MDPI, 2025-09-02) Castañé Vilafranca, Helena; Jiménez Franco, Andrea; Onoiu, Alina Iuliana; Cambra Cortés, Vicente; Hernández Aguilera, Anna; Parada Domíngues, David; Riu, Francisco; Zorzano Olarte, Antonio; Camps, Jordi; Joven, Jorge
We investigated the impact of liver damage on systemic inter-organ communication in an extensive observational case-control study of 923 patients with severe obesity and biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH) undergoing bariatric surgery. Using a comprehensive panel of circulating organokines, including fibroblast growth factor (FGF) 19, FGF21, adiponectin, galectin-3, irisin, and leptin, along with choline metabolites, we characterized metabolic signaling patterns associated with liver disease severity. Compared to controls, patients with MASLD/MASH exhibited significantly lower levels of FGF19, choline, and trimethylamine, while FGF21, galectin-3, irisin, and leptin were elevated. Sex-specific alterations in leptin and adiponectin were observed in patients with severe obesity but not in controls. Network analysis revealed a complex and individualized interplay among organokines, shaped by age, sex, and anthropometric factors. Despite this complexity, a dysregulation of the FGF21-adiponectin axis was associated with more advanced liver involvement. The large cohort and comprehensive organokine profiling studied provide valuable insights into the role of the FGF21-adiponectin axis on systemic metabolic alterations in severe obesity and their potential clinical implications.
A bioinformatics screen identifies TCF19 as an aggressiveness-sustaining gene in prostate cancer
(FEBS Press, 2025-09-15) Ercilla Eguiarte, Amaia; Crespo, Jana R.; García Longarte, Saioa; Fidalgo, Marta; Palacio, Sara del; Martín Martín, Natalia; Carlevaris, Onintza; Astobiza, Ianire; Fernández Ruiz, Sonia; Guiu Comadevall, Marc; Bárcena, Laura; Mendizabal, Isabel; Aransay, Ana M.; Graupera i Garcia-Milà, Mariona; Gomis i Cabré, Roger; Carracedo, Arkaitz
Prostate cancer is a prevalent tumor type that, despite being highly curable, progresses to metastatic disease in a fraction of patients, thus accounting for more than 350 000 annual deaths worldwide. In turn, uncovering the molecular insights of metastatic disease is instrumental in improving the survival rate of prostate cancer patients. By means of gene expression meta-analysis in multiple prostate cancer patient cohorts, we identified a set of genes that are differentially expressed in aggressive prostate cancer. Transcription factor 19 (TCF19) stood out as an unprecedented epithelial gene upregulated in metastatic disease, with prognostic potential and negatively associated with the activity of the androgen receptor. By combining computational and empirical approaches, our data revealed that TCF19 is required for full metastatic capacity, and its depletion influences core cancer-related processes, such as tumor growth and vascular permeability, supporting the role of this gene in the dissemination of prostate tumor cells.
Regulatory Mechanisms of SPARC Overexpression in Melanoma Progression
(MDPI, 2025-09-08) Vinyals, Antònia; Ferreres Riera, Jose Ramon; Campos Martín, Rafael; Jorge Torres, Olga C.; Mainez Villoro, Jessica; Puig Butillé, Joan Anton; Marcoval Caus, Joaquim; Puig i Sardà, Susana; Fabregat Romero, Isabel; Fabra Fres, Àngels
The expression of the Secreted Protein, Acidic and Rich in Cysteine (SPARC) gene in human melanoma increases during progression and is associated with epithelial-to-mesenchymal transition (EMT), which is a major determinant of metastasis in melanoma patients. However, the underlying molecular mechanisms that control SPARC expression in this context remain elusive. Herein, we identified Paired-related homeobox 1 (PRRX1), an EMT transcription factor, as a transcriptional activator of SPARC by direct binding to the promoter, thereby increasing its activity. Moreover, we found a strong positive correlation between SPARC and PRRX1 expression levels in clinical samples and cell lines. Furthermore, the switch from the proliferative/melanocytic phenotype toward the invasive/mesenchymal-like phenotype favors the expression of TCF7L2, a beta-catenin cofactor, which, together with Sp1, binds to the proximal SPARC promoter, thereby bolstering protein expression. We also show that SPARC is a target of the miR-29 family, whose members are expressed in clinical melanoma samples and cell lines. Indeed, we found that miR-29b1 similar to a expression is inversely correlated with SPARC levels, and it is significantly reduced in samples with a mesenchymal-like phenotype. Taken together, SPARC expression in melanoma cells relies on transcriptional activation by PRRX1/TCF7L2-Sp1 and is modulated through miR-29b1 similar to a, which provides fine-tuning regulation over the switch between phenotypic states.

Examinar

Enviaments recents