Biology subjects

Fontes, M.

Publications and source records attributed to Fontes, M..

10 recordsLinked to original sources

bioRxiv2026

HUMAN-LIKE SIALOME REMODELING LINKS HYPERGLYCEMIA TO COLORECTAL CANCER PROGRESSION

The evolutionary loss of cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) abolished endogenous N-glycolylneuraminic acid (Neu5Gc) synthesis in humans, reshaping the sialic acid at the cell surface glycans and influencing immune and metabolic processes. However, whether a human-like sialome modulates the impact of metabolic stress on colorectal cancer (CRC) progression remains unclear. Here, we investigated the diabetes-sialome-tumor axis using a spontaneous CRC model combining conditional Apc mutation with Cmah deficiency, thereby recapitulating the human sialic acid repertoire. Under euglycemic conditions, CPC-Apc Cmah-/- mice exhibited reduced polyp numbers and tumor burden compared with WT mice, accompanied by remodeling of the tumor immune microenvironment, including increased tumor-infiltrating leukocytes, enrichment of B cells, and reduced PD-1 expression in B cells and cytotoxic CD8+ T cells. Induction of chronic hyperglycemia with low-dose streptozotocin revealed a striking genotype-specific effect. Despite comparable hyperglycemia between genotypes, tumor progression was dramatically exacerbated exclusively in Cmah-/- mice, with increased tumor burden, accelerated lesion development, and progression toward high-grade dysplasia. Histopathological analyses further revealed increased mesenchymal expansion and close resemblance to colorectal tumors from diabetic patients. Together, these findings demonstrate that a human-like sialome increases susceptibility to metabolic stress and identify CPC-Apc Cmah-/- mice as a translationally relevant model for investigating diabetes-associated colorectal carcinogenesis.

cancer biology↗

bioRxiv2025

Distributed Biomarker Discovery for Immuno-Oncology

BackgroundIdentifying robust predictive biomarkers for immuno-oncology (IO) therapy response remains challenging due to the complexity of tumor host interactions and the limited availability of public datasets. While achieving clinical relevance requires biomarkers that generalize across diverse datasets, privacy concerns surrounding sensitive clinical and molecular data further restrict data sharing, impeding progress in biomarker discovery. Materials and MethodsWe developed a scalable, cloud-based distributed pipeline, implemented as an in-silico simulation of federated learning, to enable privacy-preserving integration of clinical and molecular data across institutions. This approach supports the development of genomic prediction algorithms without sharing sensitive patient data. Using curated gene expression profiles, we evaluated the association of tumor microenvironment and IO gene expression signatures with clinical outcomes across pan-cancer, cancer-specific, and treatment-specific settings, and developed a multivariable distributed model to predict IO response. ResultsWe implemented an integrated meta-analysis pipeline using harmonized data across 18 datasets comprising 967 patients and seven cancer types treated with PD-1/PD-L1, CTLA-4, or combination immunotherapies. This approach identified biomarkers specific to lung cancer and CTLA-4 therapy previously unreported in pan-cancer and pan-IO analyses, highlighting the value of context-specific associations. Similar gene expression signatures were associated with progression-free survival and response in both pan-cancer and melanoma datasets, with notable overlap between dual checkpoint blockade and PD-1/PD-L1 therapies. Distributed multivariable XGBoost models outperformed the average of locally trained models, indicating improved generalizability. ConclusionWe present a new distributed pipeline for biomarker discovery in immuno-oncology that preserves patient privacy through federated analysis and secure data handling. This study highlights the importance of larger, diverse datasets to refine cancer- and treatment-specific biomarkers, paving the way for more precise and personalized IO therapies.

bioinformatics↗

bioRxiv2025

Bifunctional Phagocytic Synapse Enhancers for Cancer Immunotherapy

Immunotherapy profoundly impacted cancer treatments by harnessing the patients immune system. Phagocytosis, the process whereby immune cells engulf and destroy foreign particles or cells, plays a critical role in tumour cell clearance. Herein, we introduce a novel concept termed "ENPHASYS" - Enhancement of Phagocytic Synapses - designed to direct and amplify phagocytosis of cancer cells using heterobifunctional molecules named phagocytic synapse enhancers (PSEs). By engineering a de novo PD-L1 binder linked to a natural phagocytosis promoting peptide, tuftsin, the resulting PSE combines PD-L1 blockade with enhanced tumour cell phagocytosis; in addition, the PSEs induce macrophages to internalize a membrane or extracellular target. Intratumoural treatment of colorectal carcinoma- or glioblastoma-burdened immunocompetent animals resulted in beneficial overall survival, delayed tumour growth and a potent antitumor response driven by T-cell activation and TAM reprogramming, underpinning the translational relevance of ENPHASYS. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/642658v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1673fd4org.highwire.dtl.DTLVardef@18fa319org.highwire.dtl.DTLVardef@11cf680org.highwire.dtl.DTLVardef@7b8784_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

The cellular state space of AML unveils novel NPM1 subtypes with distinct clinical outcomes and immune evasion properties

Acute myeloid leukemia (AML) is a genetically and cellularly heterogeneous disease. We characterized 120 AMLs using genomic and transcriptomic analyses, including single-cell RNA sequencing. Our results reveal an extensive cellular heterogeneity that distorts the bulk transcriptomic profiles. Selective examination of the transcriptional signatures of >90,000 immature AML cells identified four main clusters, thereby extending current genomic classification of AML. Notably, NPM1 mutated AML could be stratified into two novel, clinically relevant classes, with NPM1class I associated with downregulation of MHC class II and excellent survival following hematopoietic stem cell transplantation (HSCT). NPM1class II was instead associated with resistance to allogeneic T cells in an ex vivo co culture assay, and importantly, dismal survival following HSCT. These findings provide new insights into the cellular state space of AML, define new diagnostic entities, and highlight potential therapeutic intervention points. Key PointsO_LIThe bulk transcriptional profiles of AML are mainly driven by a diverse set of cellular signatures. C_LIO_LISingle cell RNA-sequencing of the most common AML subtypes reveals marked heterogeneity extending beyond current genomic classification schemes. C_LIO_LINPM1-mutated AML can be divided into two new classes, with distinct immune evasion mechanisms and survival after transplantation. C_LI

cancer biology↗

bioRxiv2024

The two crystal structures of unloaded and cargo-loaded Vacuolar Sorting Receptor 1 lumenal domain (VSR1-Nt) reveal two cargo binding sites and a mechanism of transport.

Vacuolar sorting receptors (VSRs) are type I membrane proteins crucial for seed germination and plant development. While VSR trafficking has been extensively studied, the mechanism of cargo binding and release by the N-terminal lumenal region is less understood. We have elucidated the crystal structures of unloaded and cargo-loaded forms of the lumenal region of VSR1 containing the protease-associated domain, the Central domain and epidermal growth factor-like repeats. Calcium coordination induces remodeling of the linkers between domains, triggering large conformational changes that expose two binding sites, one across the PA and Central domain and a second site in the Central domain. Our findings provide a mechanistic model for cargo binding in a calcium rich environment, where VSR is locked in a conformation exposing the cargo binding sites, while cargo release is favoured by lower calcium concentrations and trimer formation. These results advance our current knowledge on VSRs and will inform future studies on vacuolar trafficking and cargo binding/release.

plant biology↗

bioRxiv2024

Macrophages drive the earliest anti-tumoral response to BCG therapy by directly killing bladder cancer through TNF signaling

The Bacillus Calmette-Guerin (BCG) vaccine is the cancer immunotherapy longest in use. Despite its effectiveness in bladder cancer (BC), its initial mechanisms of action remain largely unknown. Therefore, proper diagnostic assessments to identify patients who will not respond to treatment or develop resistance are lacking. Here, we set-out to unravel the earliest innate cellular mechanisms involved in BCG-induced clearance of tumors. We show that BCG induces a massive recruitment of macrophages to the tumor microenvironment and modulates their morphology and behavior towards a proinflammatory phenotype, while also promoting macrophage fusion-like events. We demonstrate that macrophages directly induce apoptosis and clearance of cancer cells through TNF-signaling and that they are indispensable for this antitumoral response since their depletion completely abrogates the BCG-anti tumor effect. Contrary to the general concept that macrophage antitumoral activities uniquely rely on stimulating an effective adaptive response, we demonstrate that macrophages alone can directly induce tumor killing and clearance; revealing an additional step to the BCG-induced tumor immunity model, that was not previously considered. In addition, we also provide proof-of-concept experiments demonstrating the potential of this unique in vivo preclinical model to test new innate immunomodulators.

cancer biology↗

bioRxiv2019

Polygenic Risk for Skin Autoimmunity Impacts Immune Checkpoint Blockade in Bladder Cancer

PD-1 and PD-L1 act to restrict T-cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti-PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti-PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti-PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti-PD-L1 monotherapy in bladder cancer.

genetics↗

bioRxiv2019

Hyperglycemia enhances cancer immune evasion by inducing alternative macrophage polarization through increased O-GlcNAcylation

Diabetes mellitus (DM) significantly increases the risk for cancer and cancer progression. Hyperglycemia is the defining characteristic of DM and tightly correlates with a poor prognosis in cancer patients. The hexosamine biosynthetic pathway (HBP) is emerging as a pivotal cascade linking high glucose, tumor progression and impaired immune function. Here we show that enhanced glucose flow through the HBP drives cancer progression and immune evasion by increasing O-GlcNAcylation in tumor-associated macrophages (TAMs). Increased O-GlcNAc skewed macrophage polarization to a M2-like phenotype. HBP or O-GlcNAcylation inhibition reprogrammed TAMs to an anti-tumoral phenotype. Finally, we found an upregulation of M2 markers on TAMs in DM2 patients with colorectal cancer compared to non-diabetic normoglycemic patients. Our results provide evidence for a new and targetable mechanism of cancer immune evasion in patients with hyperglycemia, advocating for strict control of hyperglycemia in cancer patients.\n\nSignificanceHyperglycemia increases O-GlcNAc levels in TAMs, programing them to a pro-tumorigenic phenotype (M2-like), contributing to cancer progression. Inhibition of O-GlcNAcylation could therefore be used to reprogram intratumoral macrophages to an anti-tumoral phenotype.

cancer biology↗

bioRxiv2018

Sex differences in IL-17 determine chronicity in male versus female urinary tract infection

Sex-based differences influence incidence and outcome of infectious disease. Women have a significantly greater incidence of urinary tract infection (UTI) than men, yet, conversely, male UTI is more persistent with greater associated morbidity. Mechanisms underlying these sex-based differences are unknown, in part due to a lack of experimental models. We optimized a model to transurethrally infect male mice and directly compared UTI in both sexes. Although both sexes were initially equally colonized by uropathogenic E. coli, only male and testosterone-treated female mice remained chronically infected for up to 4 weeks. Female mice had more robust innate responses, including higher IL-17 expression, and increased {gamma}{delta} T and LTi-like cells in the bladder following infection. Accordingly, neutralizing IL-17 abolished resolution in female mice, identifying the cytokine pathway necessary for bacterial clearance. Our findings support the concept that sex-based responses to UTI contribute to impaired innate immunity in males and provide a rationale for non-antibiotic-based immune targeting to improve the response to UTI.\n\nOne Sentence SummaryWe investigated mechanisms underlying the clinical observation that while urinary tract infection is more prevalent in women, it is more severe in men, observing that in contrast to robust immune responses characterized by IL-17 in female animals, male mice develop chronic infection, following a failure to initiate innate immunity.

immunology↗

bioRxiv2018

DISSEQT - DIStribution based modeling of SEQuence space Time dynamics

Rapidly evolving microbes are a challenge to model because of the volatile, complex and dynamic nature of their populations. We developed the DISSEQT pipeline (DIStribution-based SEQuence space Time dynamics) for analyzing, visualizing and predicting the evolution of heterogeneous biological populations in multidimensional genetic space, suited for population-based modeling of deep sequencing and high-throughput data. DISSEQT is openly available on GitHub (https://github.com/rasmushenningsson/DISSEQT.jl) and Synapse (https://www.synapse.org/#!Synapse:syn11425758), covering the entire workflow from read alignment to visualization of results. DISSEQT is centered around robust dimension and model reduction algorithms for analysis of genotypic data with additional capabilities for including phenotypic features to explore dynamic genotype-phenotype maps. We illustrate its utility and capacity with examples from evolving RNA virus populations, which present on of the highest degrees of population heterogeneity found in nature. Using DISSEQT, we empirically reconstruct the evolutionary trajectories of evolving populations in sequence space and genotype-phenotype fitness landscapes. We show that while sequence space is vastly multidimensional, the relevant genetic space of evolving microbial populations is of intrinsically low dimension. In addition, evolutionary trajectories of these populations can be faithfully monitored to identify the key minority genotypes contributing most to evolution. Finally, we show that empirical fitness landscapes, when reconstructed to include minority variants, can predict phenotype from genotype with high accuracy.

evolutionary biology↗