Biology subjects

Seoane, J.

Publications and source records attributed to Seoane, J..

9 recordsLinked to original sources

bioRxiv2026

sabinaMBM: An R package for Multiscale Bayesian species distribution Modelling using INLA

1. Regional species distribution models (SDM) calibrated over spatially restricted extents tend to truncate species' ecological niches. Existing nested SDM workflows integrate multi-scale information through sequential combination, which limits formal uncertainty propagation across scales and prevents regional predictions from being explicitly constrained within globally-informed niche boundaries. 2. We introduce sabinaMBM, an R package implementing joint multiscale Bayesian SDM within a unified probabilistic framework built on inlabru/R-INLA. It propagates uncertainty across scales without the computational bottlenecks of MCMC-based approaches. The framework offers multiple coupling architectures ranging from complete independence to hierarchical constraint that can be configured independently for intercepts and covariates. 3. In a range-margin population, hierarchical constraint most improves out-of-sample discrimination where regional data were scarcest, while leaving predictions unchanged where they already suffice, delivering gains precisely where sequential approaches are expected to struggle most. Applied to Quercus petraea across its Iberian trailing-edge, including a spatial field produced the largest single performance gain, consistent across every coupling configuration, and covariate responses diverged by scale for at least one climatic predictor. Under future climate, the constrained model yielded lower suitable habitat estimates and redistributed uncertainty in proportion to cross-scale agreement rather than uniformly. 4. sabinaMBM makes multiscale Bayesian inference accessible without specialist programming. This framework provides robust value for trailing-edge populations and spatial (invasive species) or temporal (climate change) projections where niche truncation risks ecologically implausible outcomes, while simultaneously delivering fine-resolution predictions with properly propagated uncertainty whenever global and regional covariates offer complementary information.

ecology↗

bioRxiv2026

C1q from C1q+ tumor-associated myeloid cells promotes resistance to T-cell engagers and CAR T-cells and is induced by LIF and glucocorticoids

Immunotherapies, particularly T-cell engagers (TCEs) and CAR T-cells, have shown limited efficacy in solid tumors, partly due to an immunosuppressive tumor microenvironment (TME). However, the molecular mechanisms by which the TME impairs immunotherapy remain poorly understood. Here, we found that C1q generated by C1q tumor-associated myeloid cells (TAMs) plays a fundamental role in shaping the immunosuppressive TME in glioblastoma (GBM), one of the most aggressive tumors. C1q suppressed T-cell activation and impaired the activity of T-cell engagers (TCEs) and CAR T-cells. Genetic ablation of C1qa improved anti-tumor responses to TCEs and CAR T-cells. We used innovative patient-derived tumor tissue cultures (PDTTCs), which preserve an intact TME, from 19 GBM patients and identified the LIF cytokine as the main inducer of C1q. Moreover, we discovered that glucocorticoids cooperate with LIF to induce C1q. The identified C1q TAM signature overlapped with an anti-LIF gene signature, was associated with poor prognosis, and was enriched in mesenchymal GBMs with NF1 mutations. The blockade of LIF using an anti-LIF neutralizing antibody decreased the presence of C1q+ TAMs, and we found that the regulation of C1q by anti-LIF is conserved between human and mouse. Using the C1qa-/- GBM mouse model, we showed that C1q mediates the anti-tumor immune response induced by LIF blockade. Our findings identify C1q TAMs as key immunosuppressive players in GBM, impairing CAR T-cells and TCE activity, and position them as therapeutic targets to improve immunotherapy responses in this devastating disease.

cancer biology↗

bioRxiv2023

IKK1 kinase coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy

Activation of the IKK kinase complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF-{kappa}B has remained elusive. Analysis of IKK-dependent substrates after UV-treatment revealed that BRD4 phosphorylation by IKK is required for chromatin-binding dynamics upon damage. Moreover, IKK induces the NF-{kappa}B-dependent transcription of LIF leading to STAT3 activation, association of BRD4 to STAT3 and recruitment to specific target genes. IKK abrogation results in defective BRD4 and STAT3 function leading to irreparable DNA damage and apoptotic cell death upon different stimuli. Simultaneous inhibition of BRAF-dependent IKK activity or BRD4 and the JAK/STAT pathway enhanced the therapeutic potential of 5-FU plus irinotecan in CRC cells, and is curative in a chemotherapy-resistant CRC xenograft model. Coordinated expression of LIF and IKK is a poor prognosis marker for CRC patients. Our data uncover a functional link between IKK, BRD4 and JAK/STAT signaling with clinical relevance.

cancer biology↗

bioRxiv2021

Pan-cancer organoid validation of tumor outlier chromosomal amplification events

Somatic copy number gains are pervasive in many cancer types, yet their roles in oncogenesis are often poorly explored. This lack of understanding is in part due to broad extensions of copy gains across cancer genomes spanning large chromosomal regions, obscuring causal driver loci. Here we employed a multi-tissue pan-organoid modeling approach to validate candidate oncogenic loci identified within pan-cancer TCGA data by the overlap of extreme copy number amplifications with extreme expression dysregulation for each gene. The candidate outlier loci nominated by this integrative computational analysis were functionally validated by infecting cancer type-specific barcoded full length cDNA lentiviral libraries into cognate minimally transformed human and mouse organoids bearing initial oncogenic mutations from esophagus, oral cavity, colon, stomach, pancreas and lung. Presumptive amplification oncogenes were identified by barcode enrichment as a proxy for increased proliferation. Iterative analysis validated DYRK2 at 12q15, encoding a serine-threonine kinase, as an amplified head and neck squamous carcinoma oncogene in p53-/- oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, was validated in p53-/- esophageal organoids in vitro and in vivo with pharmacologic inhibition by small molecule and soluble receptor FGFR antagonists. Our studies establish the feasibility of pan-organoid contextual modeling of pan-cancer candidate genomic drivers, enabling oncogene discovery and preclinical therapeutic modeling.

cancer biology↗

bioRxiv2020

A Single-Cell Tumor Immune Atlas for Precision Oncology

The tumor immune microenvironment is a main contributor to cancer progression and a promising therapeutic target for oncology. However, immune microenvironments vary profoundly between patients and biomarkers for prognosis and treatment response lack precision. A comprehensive compendium of tumor immune cells is required to pinpoint predictive cellular states and their spatial localization. We generated a single-cell tumor immune atlas, jointly analyzing >500,000 cells from 217 patients and 13 cancer types, providing the basis for a patient stratification based on immune cell compositions. Projecting immune cells from external tumors onto the atlas facilitated an automated cell annotation system for a harmonized interpretation. To enable in situ mapping of immune populations for digital pathology, we applied SPOTlight, combining single-cell and spatial transcriptomics data and identifying striking spatial immune cell patterns in tumor sections. We expect the tumor immune cell atlas, together with our versatile toolbox for precision oncology, to advance currently applied stratification approaches for prognosis and immuno-therapy.

cancer biology↗

bioRxiv2020

Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures

Deep sequencing of B cell receptor (BCR) heavy chains from a cohort of 19 COVID-19 patients from the UK reveals a stereotypical naive immune response to SARS-CoV-2 which is consistent across patients and may be a positive indicator of disease outcome. Clonal expansion of the B cell memory response is also observed and may be the result of memory bystander effects. There was a strong convergent sequence signature across patients, and we identified 777 clonotypes convergent between at least four of the COVID-19 patients, but not present in healthy controls. A subset of the convergent clonotypes were homologous to known SARS and SARS-CoV-2 spike protein neutralising antibodies. Convergence was also demonstrated across wide geographies by comparison of data sets between patients from UK, USA and China, further validating the disease association and consistency of the stereotypical immune response even at the sequence level. These convergent clonotypes provide a resource to identify potential therapeutic and prophylactic antibodies and demonstrate the potential of BCR profiling as a tool to help understand and predict positive patient responses.

immunology↗

bioRxiv2019

The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness.

Classification of gliomas as wild-type or mutant IDH1/2 tumors has profound clinical implications. However, how these two groups of gliomas progress, in a microenvironment-dependent manner, is still a pending question. Here we describe that the expression of Tau is epigenetically induced by mutant IDH1/2, whereas is almost absent from tumors with EGFR/PTEN mutations. Moreover, Tau (MAPT) expression is inversely correlated with overall survival in EGFR-amplified gliomas. Using orthotopic EGFR-related models, we have observed that Tau overexpression or microtubule stabilizers impair the mesenchymal transformation of glioma cells, with profound changes in tumor vasculature and a significant decrease in tumor burden. However, epithelial-to-mesenchymal transformed EGFR-mutant cells, acting as pericytes, induce neo-vasculogenesis and favor aggressive glioma growth, a process that is no longer sensitive to Tau. Altogether our data indicate that the genomic background controls glioma aggressiveness by modifying the vascular microenvironment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/541326v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1c4b33forg.highwire.dtl.DTLVardef@d3f636org.highwire.dtl.DTLVardef@1c957c1org.highwire.dtl.DTLVardef@1a04a0d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

Spatial patterns of species richness and nestedness in ant assemblages along an elevational gradient in a Mediterranean mountain range

The study of biodiversity spatial patterns along ecological gradients can serve to elucidate factors shaping biological community structure and predict ecosystem responses to global change. Ant assemblages are particularly interesting as study cases, because ant species play a key role in many ecosystem processes and have frequently been identified as useful bioindicators. Here we analyzed the response of ant species richness and assemblage composition to elevational gradients in Mediterranean grasslands and subsequently tested whether these responses were stable spatially and temporally. We sampled ant assemblages in two years (2014, 2015) in two mountain ranges (Guadarrama, Serrota) in Central Spain, along an elevational gradient ranging from 685 to 2390 m a.s.l.\n\nJackknife estimates of ant species richness ranged from three to 18.5 species and exhibited a hump-shaped relationship with elevation that peaked at mid range values (1100 - 1400 m). This pattern was transferable temporally and spatially. Elevation was significantly related to ant assemblage composition and facilitated separation of higher elevation assemblages (> 1700 m) from the remaining lower elevation species groups. Ant assemblages were nested; therefore species assemblages with a decreased number of species were a subset of the richer assemblages, although species turnover was more important than pure nestedness in all surveys. The degree of nestedness changed non-linearly as a cubic polynomial with elevation. These assembly patterns were observed over time but not between the two study regions.\n\nWe concluded double environmental stressors typical of Mediterranean mountains explained species richness patterns: drought at low elevations and cold temperatures at high elevations likely constrained richness at both extremes of elevational gradients. The fact that species turnover showed a dominant role over pure nestedness suggested current ant assemblages were context-dependent (spatio-temporal factors) and highly vulnerable to global change, which threatens the conservation of present day native ant communities, particularly at high elevations.

ecology↗

bioRxiv2018

Subjugation of TGFβ Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End-Joining

Purpose: Following cytotoxic therapy, 70% of patients with human papillomavirus (HPV) positive oropharyngeal head and neck squamous cell carcinoma (HNSCC) are alive at 5 years compared to 30% of those with similar HPV-negative cancer, which is thought to be due to dysregulation of DNA repair. Loss of transforming growth factor {beta} (TGF{beta}) signaling is a poorly studied consequence of HPV that could contribute to this phenotype.\n\nExperimental Design: Human HNSCC cell lines (n=9), patient-derived xenografts (n=9), tissue microarray (n=194), TCGA expression data and primary tumor specimens (n=10) were used to define the relationship between TGF{beta} competency, response to DNA damage, and type of DNA repair.\n\nResults: Analysis of HNSCC specimens in situ and in vitro showed that HPV associates with loss of TGF{beta} signaling that increases the response to radiation or cisplatin. TGF{beta} suppressed miR-182 that inhibited both BRCA1, necessary for homologous recombination repair, and FOXO3, which is required for ATM kinase activity. TGF{beta} signaling blockade by either HPV or inhibitors released this control, compromised HRR and increased response to PARP inhibition. Antagonizing miR-182 rescued the homologous recombination deficit in HPV+ cells. Loss of TGF{beta} signaling unexpectedly increased error-prone, alternative end-joining repair.\n\nConclusions: HPV-positive HNSCC cells are unresponsive to TGF{beta}. Abrogated TGF{beta} signaling compromises homologous recombination and shifts reliance on alt-EJ repair that provides a mechanistic basis for sensitivity to PARP inhibitors. The effect of HPV in HNSCC provides critical validation of TGF{beta}s role in DNA repair proficiency and further raises the translational potential of TGF{beta} inhibitors in cancer therapy.

cancer biology↗