Biology subjects

Abad, E.

Publications and source records attributed to Abad, E..

6 recordsLinked to original sources

bioRxiv2026

Nuclear adenosine metabolism defines a metabolic vulnerability unmasked by TP53 loss

Metabolic adaptation is essential for cells experiencing chronic genomic stress, yet how such adaptations are organized at the nuclear level remains poorly understood. Loss of TP53 is associated with elevated genomic instability, DNA damage and altered metabolic requirements, creating context specific dependencies. Here, we identify a requirement for de novo purine biosynthesis in TP53-deficient cells, with a pronounced dependence on adenosine related metabolism. Perturbation of purine synthesis increases DNA damage and reduces nuclear ATP availability, particularly in TP53-deficient cells, and is accompanied by a rapid increase in histone methylation. This chromatin response is also induced by acute DNA damage and occurs with fast kinetics, indicating that histone methylation is an early, intrinsic feature of the nuclear stress response rather than a secondary epigenetic remodeling. Interfering with histone methylation is associated with reduced nuclear ATP levels and impaired DNA damage resolution, linking chromatin state to nuclear energy homeostasis. Genetic disruption of the purine biosynthesis enzyme PFAS selectively impairs the growth of TP53-deficient tumours in vivo, establishing the physiological relevance of this metabolic dependency. Together, these findings reveal nuclear adenosine metabolism as a compartmentalised adaptive response to genotoxic stress and highlight chromatin associated methylation as a key feature of nuclear metabolic regulation unmasked by TP53 loss.

cancer biology↗

bioRxiv2025

Dual inhibition of the nonsense mediated mRNA decay enhances tumour immunogenicity, drives immunoediting, and potentiates checkpoint blockade

Immune checkpoint blockade has transformed cancer therapy, but current biomarkers such as tumour mutation burden often fail to reliably predict clinical benefit. One proposed reason for this discrepancy is the activity of nonsense-mediated mRNA decay (NMD), a cellular quality-control pathway that degrades mutant transcripts, potentially reducing the presentation of neoantigens that would otherwise stimulate anti-tumour immunity. To address this, we identified publicly available small-molecule inhibitors targeting the NMD factors SMG5 and SMG7 (NMDi), which we have prioritise as the NMD components most strongly associated with NMD efficiency across TCGA tumours, and evaluated their therapeutic potential in vivo. In a syngeneic, DNA repair deficient mouse model of lung adenocarcinoma, NMDi treatment alone substantially reduced tumour burden, and its combination with anti-PD-1 therapy led to additive benefit either treatment alone. These effects were immune-dependent and specifically required CD8{square} T cells. Transcriptomic and single-cell analyses revealed that NMDi reprograms the tumour immune microenvironment, enriching for clonally expanded, cytotoxic CD8{square} T cells and altering macrophage states toward those associated with tumour regression. Whole-genome sequencing of tumours revealed that NMDi also promotes immunoediting, leading to negative selection against immunogenic mutations and coding indels, with selective pressure comparable to or greater than that induced by anti-PD-1 treatment. Guided by these results, we generated a new protein language model trained on tumour mutations that can identify neopeptides with immunogenic properties, revealing that the NMDi tumour landscape provides a rich genomic and immunopeptidomic setting for exposing neoantigens that evade immunoediting. Together, these pre-clinical and integrative genomic-transcriptomic insights position NMD inhibition as a promising immunostimulatory strategy that can potentiate immune checkpoint blockade efficacy in tumours.

cancer biology↗

bioRxiv2025

Site-specific immunogenicity and anti-PD1 response in mismatch repair deficient lung adenocarcinoma models

Immunotherapy has revolutionized cancer treatment, yet responses vary significantly based on tumour characteristics and microenvironment. Here, we developed and analysed subcutaneous and orthotopic immunocompetent mice models of mismatch repair-deficient (dMMR) lung adenocarcinoma (LUAD) by selectively ablating Mlh1. Subcutaneous tumours demonstrated partial sensitivity to anti-PD1 therapy, characterized by tumour volume reduction without significant changes in immune infiltration. In contrast, orthotopic tumours exhibited robust responses, with substantial reductions in tumour burden, enhanced immune infiltration, and increased CD4+ memory T cells, highlighting the critical role of anatomical site and tumour microenvironment in shaping immunotherapy outcomes. Our findings emphasise the relevance of orthotopic models for preclinical evaluation and suggest that they more accurately reflect clinical responses to immune checkpoint blockade in dMMR LUAD.

cancer biology↗

bioRxiv2020

Spatio-temporal analysis at landscape scale of the Iberian oak decline epidemic caused by Phytophthora cinnamomi

Phytophthora cinnamomi Rands is considered a main factor behind the Iberian oak decline (IOD). This epidemic is decimating Holm oaks (Quercus ilex L.) and cork oaks (Quercus suber L.) which are the keystone trees of a multipurpose, silvo-pastoral and semi-natural ecosystem of 3.1 million hectares in the south west of Europe. Forest diseases are characterized by pronounced spatial patterns, since many of the underlying ecological processes are inherently spatial. To improve the current understanding of such processes, we carried out a complete census of diseased sites via aerial imagery at landscape scale at four different dates over a period of 35 years. We validated our photographic interpretation of P. cinnamomi presence in-situ by subsampling soil and roots of diseased sites. To analyse the role of host population heterogeneities in shaping the spread of IOD, we used a self-exciting spatio-temporal point process model. Its so-called epidemic component represents the inoculum pressure arising from nearby foci whereas its background component allows for sporadic infections from unobserved sources or disease transmission over larger distances. The best fit was obtained with a lagged power-law for the spatial dispersal kernel, where 49% of the infections triggered by an infected site occur within a distance of 250 meters. Both risk components were found to increase over time. The rate of sporadic infections appeared to be significantly lower in silvo-pastoral systems (dehesas) than in forests and higher in mixed stands and shrub encroached oak-lands. These results may have direct implications for IOD management, for example, the estimated spatial dispersal function helps to define a suitable target area for more efficient control measures. Our results also suggest that silviculture treatments aimed at controlling the density and species composition of oak stands, as well as the abundance of shrubs, could play a key role for disease management

plant biology↗

bioRxiv2018

Topographic effects on dispersal patterns of Phytophthora cinnamomi at a stand scale in a Spanish heathland

Phytophthora cinnamomi is one of the most important plant pathogens in the world, causing root rot in more than a thousand plant species. This observational study was carried out on a P. cinnamomi infected heathland of Erica umbellata used as goat pasture. The patterns and shapes of disease foci and their distribution were described in a spatial and temporal context using an aerial photograph record. A set of topographic traits was selected on the basis of a disease dynamic hypothesis and their effects on observed spatial disease patterns were analyzed. Incipient infections situated in flat terrain expanded as compact circular front patterns with a low growth rate. On slopes, disease patches developed more rapidly down slope, forming parabolic shapes. The axis direction of the parabolas was highly correlated with terrain aspect, while the parabolic amplitude was associated with land curvature and slope. New secondary foci appeared over the years producing an accelerated increase of the affected surface. These new foci were observed in sites where disease density was higher or near sites more frequently visited by animals such as the stable or the forage crop. In contrast, a smaller number of disease foci occur in areas which animals are reluctant to visit, such as where they have a short range of vision. Our results suggest that 1) the growth of existing P. cinnamomi foci is controlled by a combination of root-to-root contact and water flows, 2) the increase in the diseased area arises mainly from the multiplication of patches, 3) the formation of new foci is mediated by long-distance transport due to the movement of animals and humans along certain preferential pathways, and 4) geomorphology and topography traits are associated with the epidemiology of this soil-borne pathogen.

plant biology↗

bioRxiv2016

Impact of Zygosity in Bimodal Phenotype Distributions

Allele number, or zygosity, is a clear determinant of gene expression in diploid cells. But the relationship between the number of copies of a gene and its expression can be hard to anticipate, especially when the gene in question is embedded in a regulatory circuit that contains feedbacks. Here we study this question making use of the natural genetic variability of human populations, which allows us to compare the expression profiles of a receptor protein in natural killer cells between donors infected with human cytomegalovirus (HCMV) with one or two copies of the allele. Crucially, the distribution of gene expression in many of the donors is bimodal, indicative of the presence of a positive feedback somewhere in the regulatory environment of the gene. Three separate gene-circuit models differing in the location of the positive feedback with respect to the gene can all reproduce well the homozygous data. However, when the resulting fitted models are applied to the hemizygous donors, only one model (the one with the positive feedback located at the level of gene transcription) reproduces the experimentally observed gene-expression profile. In that way, our work shows that zygosity can help us relate structure and function of gene regulatory networks.\n\nAuthor SummaryNearly all mammalian cells, including human cells, have two copies of each chromosome, and thus possess two potentially different copies of each gene (which might be in some cases non-functional or even absent). Naiively one might expect that two identical copies of the gene would lead to the protein being expressed at twice the rate, but many factors can alter this simple calculation. One of these factors is the existence of feedback mechanisms affecting in one way or another the regulatory circuit in which our gene of interest is embedded. Here we study the relationship between the number of gene copies and the expression of a receptor protein that plays a crucial role in the recognition of pathogens by natural killer cells, which are important elements of the innate immune system. Experimental data of virus-infected donors reveals a bimodal expression profile of this receptor, typical of a positive feedback, and a clear difference between donors with one or two copies of the gene. Mathematical modeling allows us to find the likely location of the feedback loop within the genes regulatory circuit, by requiring the correct model to reproduce the expression profiles of both types of donors.

systems biology↗