Biology subjects

Relvas-Santos, M.

Publications and source records attributed to Relvas-Santos, M..

5 recordsLinked to original sources

bioRxiv2026

CD44-CD206 axis drives dendritic cell loss and immunosuppression in immaturely glycosylated bladder tumours

Antigen-presenting-cell dysfunction drives immune exclusion, but how tumour glycans disable these cells remains incompletely defined. Immature O-glycosylation, marked by Tn and sialyl-Tn antigens, drives myeloid dysfunction in bladder cancer. Transcriptomics and human tumour profiling linked this state to reduced representation of antigen-presenting myeloid cells and attenuated lymphoid-effector programmes. In glycoengineered models, immature O-glycans promoted immunoregulatory macrophage phenotypes and contact-dependent death of monocyte-derived dendritic cells (moDCs), while surviving cells showed impaired maturation and T-cell activation. Tumour-cell CD44 standard isoform was required for DC death, which was accompanied by inflammasome-associated proteins and gasdermin D cleavage, consistent with pyroptosis. Receptor-discovery approaches converged on CD206, which bound immaturely glycosylated CD44. CD206 blockade restored DC viability. In immunocompetent mice, immature glycosylation accelerated tumour growth and depleted conventional DCs, whereas CD206 blockade restrained tumour progression and restored local and nodal myeloid and lymphoid immunity. These findings identify CD44-CD206 as a targetable glycoimmune checkpoint that promotes immune exclusion.

immunology↗

bioRxiv2025

CD276 Immature Glycosylation Drives Colorectal Cancer Aggressiveness and T-cell Mediated Immune Escape

Colorectal cancer (CRC) progression is fueled by immune evasion, yet the underlying molecular mechanisms remain to be fully characterized. CD276 (B7-H3), an immune checkpoint glycoprotein frequently overexpressed in aggressive tumours, is extensively modified by glycosylation, a process known to regulate protein stability, localization, and immune interactions. However, its glycosylation-dependent functions in CRC remain unclear. This study shows that poor-prognosis CRC tumours exhibit dysregulated glycogene expression, leading to an immature O-glycosylation phenotype that enhances malignancy. Using C1GALT1 knockout CRC cells, which recapitulate the cancer glycocalyx, it was demonstrated that this glycosylation shift promotes proliferation and invasion. We further identify CD276 as a metastasis-associated glycoprotein whose function is shaped by O-glycan modifications. Mechanistically, immature O-glycosylation of CD276 enhances invasion, suppresses T-cell activation, and induces an immunosuppressive cytokine milieu, reinforcing its role in tumour immune escape. These findings establish CD276 as a glycosylation-dependent immune checkpoint and a promising therapeutic target to overcome immune evasion in CRC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/668091v1_ufig1.gif" ALT="Figure 1"> View larger version (101K): org.highwire.dtl.DTLVardef@2af030org.highwire.dtl.DTLVardef@fee9a8org.highwire.dtl.DTLVardef@19e1c49org.highwire.dtl.DTLVardef@152fd73_HPS_FORMAT_FIGEXP M_FIG C_FIG Table of ContentsColorectal cancer (CRC) progression is closely linked to immune evasion, yet the molecular mechanisms underlying this process remain poorly understood. This study identifies CD276 (B7-H3) as a glycosylation-driven regulator of CRC aggressiveness and demonstrates how O-glycosylation remodeling promotes tumour immune escape. These findings establish CD276 as a potential therapeutic target and highlight the role of glycoproteoform-specific immune modulation in cancer progression.

cancer biology↗

bioRxiv2025

GlycoAvatars: Bead-Coated Membrane Models for Studying the Cancer-Immune Cells Interactome

Immature O-glycosylation of plasma membrane proteins, characterized by the presence of glycosites with a single GalNAc residue (the Tn antigen) rather than more extended and complex glycans, is a prominent feature of many advanced solid tumors across different origins and aetiologies. This form of glycosylation has been strongly associated with poor prognosis and is known to play a crucial role in the progression of the disease. Notably, it has been directly implicated in the crosstalk with the immune system, inducing tolerogenic phenotypes in both innate and adaptive immune cells. Despite this, the specific receptors involved in these interactions remain largely unidentified. To address this gap, we propose a novel high-throughput proteomics assisted strategy for characterizing the glycan interactome using plasma membrane-derived glycoprotein coated magnetic beads. Glycoproteins were isolated from plasma membranes of glycoengineered cell models with immature glycosylation and were then cloaked on the surface of magnetic beads, creating simplified cell "GlycoAvatars." These GlycoAvatars were primarily employed to characterize the interactome between gastric and colorectal cancer cell lines and immune cells (dendritic cells and macrophages), providing a tool for identifying potentially relevant molecular nodes in glycan-mediated immune synapses, foreseeing their application in deciphering tumor-immune interactions.

biochemistry↗

bioRxiv2023

Multilevel Plasticity and Altered Glycosylation Drive Aggressiveness in Hypoxic and Glucose-Deprived Bladder Cancer Cells

Bladder tumours with aggressive characteristics often present with microenvironmental niches marked by low oxygen levels (hypoxia) and limited glucose supply due to inadequate vascularization. The molecular mechanisms facilitating cellular adaptation to these stimuli remain largely elusive. Employing a multi-omics approach, we discovered that hypoxic and glucose- deprived cancer cells enter a quiescent state supported by mitophagy, fatty acid {beta}-oxidation, and amino acid catabolism, concurrently enhancing their invasive capabilities. Reoxygenation and glucose restoration efficiently reversed cell quiescence without affecting cellular viability, highlighting significant molecular plasticity in adapting to microenvironmental challenges. Furthermore, cancer cells exhibited substantial perturbation of protein O-glycosylation, leading to simplified glycophenotypes with shorter glycosidic chains. Exploiting glycoengineered cell models, we established that immature glycosylation contributes to reduced cell proliferation and increased invasion. Our findings collectively indicate that hypoxia and glucose deprivation trigger cancer aggressiveness, reflecting an adaptive escape mechanism underpinned by altered metabolism and protein glycosylation, providing grounds for clinical intervention.

biochemistry↗

bioRxiv2021

Metabolomics, Transcriptomics and Functional Glycomics Reveals Bladder Cancer Cells Plasticity and Enhanced Aggressiveness Facing Hypoxia and Glucose Deprivation

Bladder cancer constitutes one of the deadliest genitourinary diseases, especially when diagnosed at late stages. These tumours harbour microenvironmental niches characterized by low levels of oxygen (hypoxia) and limited glucose supply due to poor vascularization. However, the synergic contribution of these features to disease development is poorly understood. Here, we demonstrated that cells with distinct histopathological and molecular backgrounds responded similarly to such stimuli. Cancer cells arrested proliferation, significantly increased invasive capacity in vitro and enhanced tolerance to cisplatin-based chemotherapy. Reoxygenation and access to glucose restored basal proliferation and invasion levels without triggering stress-induced apoptosis, denoting significant cellular plasticity in adapting to microenvironmental cues. Whole transcriptomics showed major molecular reprogramming, supporting main functional alterations. Metabolomics evidenced fatty acids {beta}-oxidation as main bioenergetic pathway rather than anaerobic glycolysis generally adopted by hypoxic cells. Joint pathway analysis also suggested relevant alterations in mucin-type O-glycan biosynthesis. Glycomics confirmed a major antagonization of O-glycosylation pathways, leading to simple cell glycophenotypes characterized by the accumulation of immature short-chain O-glycans such as Tn and STn antigens at the cell surface. Glycoengineered models reflecting simple cell glycophenotypes were developed and functional studies in vitro and in vivo showed that Tn and STn overexpression decreased proliferation and promoted chemoresistance, reinforcing their close link with tumour aggressiveness. Collectively, we have demonstrated that hypoxia and glucose deprivation trigger more aggressive cell behaviours, in what appears to be an escape mechanism from microenvironmental stress. We propose that, altered glycosylation may be used to target these subpopulations, paving the way for precision oncology.

cancer biology↗