Biology subjects

Cuomo, A.

Publications and source records attributed to Cuomo, A..

7 recordsLinked to original sources

bioRxiv2026

Targeting GL-Lect driven endocytosis to suppress cell plasticity in breast cancer

Aberrant endocytosis has long been associated with epithelial plasticity and tumorigenesis, but direct in vivo evidence of its causal role in tumor progression and metastasis has been lacking. Here, we identify and molecularly characterize a previously unrecognized form of E-cadherin (ECAD) internalization in mammary epithelial cells. This process is mediated by the endocytic adaptor Epsin 3 (EPN3) through glycolipid-lectin (GL-Lect) driven endocytosis requiring galectin-3 and Eps15-family adaptors. Leveraging an EPN3 knock-in mouse model, we show that dysregulation of GL-Lect driven endocytosis disrupts mammary gland morphogenesis and activates epithelial-to-mesenchymal plasticity (EMP), synergizing with the ERBB2/Neu breast oncogene to drive metastasis. Pharmacologic inhibition of the GL-Lect mechanism suppresses morphogenetic and invasive phenotypes ex vivo, providing proof-of-concept for therapeutic targeting. These findings establish the GL-Lect mechanism as a driver of metastatic plasticity and uncover a tractable vulnerability in BC.

cancer biology↗

bioRxiv2025

Endocytic control of cell-autonomous and non-cell-autonomous functions of p53

NUMB is an endocytic protein with tumor suppressor activity, largely mediated by its ability to inhibit p53 degradation. This function depends on the inclusion of a short alternatively spliced exon (Ex3) in NUMB, although the mechanistic link between endocytosis and p53 regulation remains unclear. Here, we show that the Ex3-encoded sequence directs NUMB to the plasma membrane, where it forms a complex with the endocytic adaptor SNX9. This complex recruits p53 in a SNX9-dependent manner and is internalized and trafficked to multivesicular bodies, culminating in exosomal secretion, in a process requiring both SNX9 and NUMB. Exosomal p53 is taken up by recipient cells and translocated to the nucleus, where it activates p53-dependent transcriptional and phenotypic programs. These findings suggest that exosome-mediated p53 transfer may contribute to the establishment of a tumor-suppressive microenvironment.

cancer biology↗

bioRxiv2025

METTL9 sustains vertebrate neural development primarily via non-catalytic functions

METTL9 is an enzyme catalysing N1-methylation of histidine residues (1MH) within eukaryotic proteins. Given its high expression in vertebrate nervous system and its potential association with neurodevelopmental delay, we dissected Mettl9 role during neural development. We generated three distinct mouse embryonic stem cell lines: a complete Mettl9 knock-out (KO), an inducible METTL9 Degron and a line endogenously expressing a catalytically inactive protein, and assessed their ability to undergo neural differentiation. In parallel, we down-regulated mettl9 in Xenopus laevis embryos and characterised their neural development. Our multi-omics data indicate that METTL9 exerts a conserved role in sustaining vertebrate neurogenesis. This is largely independent of its catalytic activity and occurs through modulation of the secretory pathway. METTL9 interacts with key regulators of cellular transport, endocytosis and Golgi integrity; moreover, in Mettl9KO cells Golgi becomes fragmented. Overall, we discovered the first developmental function of Mettl9 and linked it to a 1MH-independent pathway, namely, the maintenance of the secretory system, which is essential throughout neural development.

developmental biology↗

bioRxiv2024

Genetic variants associated with cell-type-specific intra-individual gene expression variability reveal new mechanisms of genome regulation

Gene expression levels can vary substantially across cells, even in a seemingly homogeneous cell population. Identifying the relationships between genetic variation and gene expression is critical for understanding the mechanisms of genome regulation. However, the genetic control of gene expression variability among the cells within individuals has yet to be extensively examined. This is primarily due to the statistical challenges, such as the need for sufficiently powered cohorts and adjusting mean-variance dependence. Here, we introduce MEOTIVE (Mapping genetic Effects On inTra-Individual Variability of gene Expression), a novel statistical framework to identify genetic effects on the gene expression variability (sc-veQTL) accounting for the mean-variance dependence. Using single-cell RNA-seq data of 1.2 million peripheral blood mononuclear cells from 980 human donors, we identified 14 - 3,488 genes with significant sc-veQTLs (study-wide q-value < 0.05) across different blood cell types, 2,103 of which were shared across more than one cell type. We further detected 55 SNP-gene pairs (in 34 unique genes) by directly linking genetic variations with gene expression dispersion (sc-deQTL) regardless of mean-variance dependence, and these genes were enriched in biological processes relevant to immune response and viral infection. An example is rs1131017 (p<9.08x10-52), a sc-veQTL in the 5UTR of RPS26, which shows a ubiquitous dispersion effect across cell types, with higher dispersion levels associated with lower auto-immune disease risk, including rheumatoid arthritis and type 1 diabetes. Another example is LYZ, which is associated with antibacterial activity against bacterial species and was only detected with a monocyte-specific deQTL (rs1384) located at the 3 UTR region (p=1.48x10-11) and replicated in an independent cohort. Our results demonstrate an efficient and robust statistical method to identify genetic effects on gene expression variability and how these associations and their involved pathways confer auto-immune disease risk. This analytical framework provides a new approach to unravelling the genetic regulation of gene expression at the single-cell resolution, advancing our understanding of complex biological processes.

genomics↗

bioRxiv2023

The cancer-specific lncRNA LISR customizes ribosomes to suppress anti-tumour immunity

Although immune checkpoint blockade (ICB) has revolutionized cancer treatment, resistance mechanisms limit its clinical benefit. Here we characterise LISRR, a cancer-specific lncRNA highly expressed in melanoma patients refractory to ICB. In cells undergoing (therapeutic) stress, LISRR recruits DAZAP1 (Deleted in AZoospermia Associated Protein 1) to polysomes and drives the assembly of a subset of ribosomes at the endoplasmic reticulum, directing the synthesis of an immunosuppressive translatome. This includes the immune checkpoint PD-L1 and the enzymes necessary for building the glycocalyx, the sugar coat surrounding the cells. Notably, proper glycocalyx assembly is required for spermatozoa immune evasion during fertilization. Accordingly, targeting LISRR activates immune responses and re-sensitizes to ICB in co-culture models, ex vivo in patient explants, and in vivo in humanized patient-derived models. Our study reveals the contribution of lncRNAs to the generation of cancer-specific ribosomes and identifies an RNA-based cancer-specific strategy to overcome intrinsic resistance to ICB.

cancer biology↗

bioRxiv2022

GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders

Copy number variations at 7q11.23 cause neurodevelopmental disorders with shared and opposite manifestations. Deletion causes Williams-Beuren syndrome (WBS), while duplication causes 7q11.23 microduplication syndrome (7Dup). Converging evidence indicates GTF2I, from the 7q11.23 locus, is a key mediator of the cognitive-behavioral phenotypes associated with WBS and 7Dup. Here we integrate molecular profiling of patient-derived cortical organoids (COs) and transgenic mouse models to dissect 7q11.23 disease mechanisms. Proteomic and transcriptomic profiling of COs revealed opposite dynamics of neural progenitor proliferation and transcriptional imbalances, leading to precocious excitatory neuron production in 7Dup. The accelerated excitatory neuron production in 7Dup COs could be rescued by GTF2I knockdown. Transgenic mice with Gtf2i duplication recapitulated early neuronal differentiation defects and ASD-like behaviors. Remarkably, inhibition of LSD1, a downstream effector of GTF2I, was sufficient to rescue ASD-like phenotypes. We propose that the GTF2I-LSD1 axis constitutes a molecular pathway amenable to therapeutic intervention.

neuroscience↗

bioRxiv2021

ProMetheusDB: an in-depth analysis of the high-quality human methyl-proteome

Protein Arginine (R) methylation is a post-translational modification involved in various biological processes, such as RNA splicing, DNA repair, immune response, signal transduction, and tumour development. Although several advancements were made in the study of this modification by mass spectrometry, researchers still face the problem of a high false discovery rate. We present a dataset of high-quality methylations obtained from several different heavy methyl SILAC (hmSILAC) experiments analysed with a machine learning-based tool doublets and show that this model allows for improved high-confidence identification of real methyl-peptides. Overall, our results are consistent with the notion that protein R methylation modulates protein:RNA interactions and suggest a role in rewiring protein:protein interactions, for which we provide experimental evidence for a representative case (i.e. NONO:PSPC1). Upon intersecting our R-methyl-sites dataset with a phosphosites dataset, we observed that R methylation correlates differently with S/T-Y phosphorylation in response to various stimuli. Finally, we explored the application of hmSILAC to identify unconventional methylated residues and successfully identified novel histone methylation marks on Serine 28 and Threonine 32 of H3.

bioinformatics↗