Biology subjects

Izzi, V.

Publications and source records attributed to Izzi, V..

14 recordsLinked to original sources

bioRxiv2026

ECMME: an atlas of selection pressures on the mammalian extracellular matrix reveals contrasting evolutionary dynamics

The extracellular matrix (ECM) is a fundamental metazoan innovation that provides structural support and regulatory cues essential for multicellular life. While core matrisome components are subject to strong functional constraints, their evolutionary dynamics at the molecular level remain incompletely characterized. Here, we present a comprehensive per-residue analysis of selection pressures across 272 human core matrisome proteins using high-quality orthologous sequences from up to 228 placental mammal species. We developed an automated pipeline integrating ortholog identification, codon-aware alignments, and site-specific selection analyses with the MEME and FUBAR methods from the HyPhy suite. Results reveal pervasive strong purifying selection across the matrisome, consistent with its structural and functional indispensability. This is accompanied by episodic positive selection and rarer pervasive positive selection, with collagens exhibiting significantly elevated episodic positive selection compared to glycoproteins and proteoglycans. To facilitate community access, we developed ECMME (ECM Molecular Evolution) browser, an intuitive open-access web resource that visualizes selection metrics plotted directly onto protein topologies. ECMME allows researchers to seamlessly browse and investigate the data, providing a powerful framework for interpreting functional sites. It is available online and requires no local installation or set-up (https://izzilab-ecmme.share.connect.posit.cloud/).

bioinformatics↗

bioRxiv2026

cran2crux: automatically create CRUX ports for R-packages

MotivationR together with CRAN and Bioconductor provides one of the richest ecosystems for bioinformatics and computational biology, with thousands of specialized packages. While GNU/Linux is a vastly-used operating system in this field, R-packages are typically managed independently of the systems native package manager. This separation makes installation, updates and mass rebuilds cumbersome. CRUX, a minimalist semi-source GNU/Linux distribution, offers great flexibility with its ports-based system for the seamless integration of R-packages with its native package manager. ResultsThe hereby presented cran2crux tool automatically generates CRUX ports for packages from both CRAN and Bioconductor. It performs recursive dependency resolution, handles naming conventions, extracts dependencies information, and supports inclusion of optional dependencies. The tool also provides convenient functions for checking updates and regenerating outdated ports. It can generate over 140 ports for complex packages such as Seurat in approximately 11 seconds, dramatically simplifying the maintenance of large R-dedicated repositories on CRUX. Availabilitycran2crux is available under the MIT license at https://github.com/izzilab/cran2crux. As of now, more than 650 R package ports, generated with the tool, are available in the CRUX ports database.

bioinformatics↗

bioRxiv2026

MatriSpace: Identification and visualization of spatially resolved ECM gene expression patterns in health and disease

The extracellular matrix (ECM) is a highly dynamic network of proteins forming the structural organizer of all tissues. Different cell populations contribute to the assembly of the 150+ proteins of a functional ECM. In addition, different ECM subtypes, supporting distinct cellular functions, are found in every organ. Spatial transcriptomics (ST) provides a unique, yet untapped, opportunity to identify which cell populations contribute to ECM production with spatial context. Applied to healthy and diseased samples, this method can identify ECM changes that could be exploited for therapeutic purposes. Here, we introduce MatriSpace, a computational framework to mine ST datasets with a focus on ECM genes. MatriSpace offers two operating modes: researchers can either upload their own ST datasets or explore a large collection of public datasets. Upon analysis, MatriSpace returns spatially resolved maps of matrisome gene expression in relation to cell populations, at multiple levels: from single-gene analysis to tissue niches and functional ECM units. MatriSpace is available as an R package and an online Shiny App (https://matrinet.shinyapps.io/matrispace), making it accessible to all users regardless of their level of expertise. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/720198v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@3f8e28org.highwire.dtl.DTLVardef@8e20beorg.highwire.dtl.DTLVardef@107be22org.highwire.dtl.DTLVardef@153b911_HPS_FORMAT_FIGEXP M_FIG C_FIG KEY POINTSO_LIMatriSpace is a computational framework to interrogate ECM gene expression in spatial transcriptomic datasets. C_LIO_LIResearchers can upload their own spatial transcriptomic datasets for processing by MatriSpace. C_LIO_LIResearchers can interrogate a vast collection of public datasets of healthy and diseased tissues through MatriSpace. C_LIO_LIMatriSpace can identify, quantify, and interpret spatial expression patterns of matrisome genes, gene sets, and niches. C_LIO_LIMatriSpace can uncover regional coordinations of matrisome components and their relationships with non-matrisome genes, such as matrisome receptors. C_LI

systems biology↗

bioRxiv2026

NaVis: a virtual microscopy framework for interactive, high-resolution navigation of spatial transcriptomics data

Despite the widespread adoption of spatial transcriptomics (ST), revealing the alignment between transcriptional layers and tissue morphology remains technically demanding, typically requiring proficiency across multiple computational frameworks and thereby limiting accessibility for a substantial fraction of the biomedical community. Here, we introduce NaVis (https://github.com/Izzilab/NaVis), a point-and-click virtual microscopy framework that redefines ST analysis as an interactive, image-centric experience. NaVis enables rapid high-resolution inference from low-resolution whole-transcriptome platforms, producing microscopy-like visualizations while preserving transcriptome-wide coverage. It further decomposes histological images into quantitative tissue architecture priors - nuclei-rich regions, fibrillar extracellular matrix, and soft tissue - allowing direct integration of gene expression with local morphology. This unified representation supports analyses of compartment enrichment, boundary concordance, spatial cross-correlation, morphological patterning, histology-expression decoupling, and transcriptome-wide spatial similarity. By coupling transcriptomic and image-derived information within an interactive framework, NaVis shifts ST from static computational workflows to an exploratory modality, broadening its accessibility, conceptual reach and potential for biological discoveries.

bioinformatics↗

bioRxiv2025

P4HA3 is abundantly expressed during early embryonic development, but does not catalyze the formation of 4-hydroxyproline in type I collagen

4-Hydroxyproline (4Hyp) is crucially important for the collagen triple helix formation and its thermal stability. It is catalyzed by collagen prolyl 4-hydroxylases (C-P4Hs) that are 2{beta}2 tetramers consisting of two identical catalytic -subunits (encoded by P4HA1, P4HA2 and P4HA3) and two {beta}-subunits that are protein disulfide isomerases (PDI). The functions of isoenzymes I and II (P4HA1 and P4HA2) are widely studied but very little is currently known about the role of P4HA3. Here we show that P4ha1 is generally the most abundant isoform in mouse, whereas P4ha3 expression is tissue and developmental stage specific. P4ha3 expression is highest in the developing skeletal system and peaks at E12.5 together with the other isoforms. Postnatal P4ha3 expression is low and mainly present in calvaria, lung, heart and muscle. The P4ha3 expression virtually disappears at or after 1 week of age in all tissues studied. To evaluate the P4HA3 function in collagen synthesis, we produced cells that lack P4HA3 (P4ha3-/-) and cells that have P4HA3 as the only isoform (P4ha1-/-;P4ha2-/-) by CRISPR/Cas9. C-P4H activity assays indicated no 4Hyp formation in type I collagen by the P4ha1-/-;P4ha2-/- cells, suggesting that the remaining isoform P4HA3 does not participate in type I collagen synthesis. The P4ha3-/- cells secreted intact pepsin-resistant collagen that had a similar 4Hyp content and melting temperature as in WT cells, and the secreted collagen assembled correctly into supramolecular collagen fibrils. In conclusion, our results provide new insights into collagen biosynthesis and suggest that prolyl 4-hydroxylation of type I collagen is mediated by P4HA1 and P4HA2 but not by P4HA3.

biochemistry↗

bioRxiv2024

Tumour-derived LAMA5 is critical for tumour initiation and controls progression and phenotype in luminal breast cancer

Basement membrane (BM) supports and regulates the structural integrity, function and differentiation of epithelial tissues and protects against breast cancer invasion to stroma. Here we show that the BM component LAMA5 is critical for initiation of luminal mammary tumours, and controls tumour progression and phenotype development. LAMA5 is overexpressed in human breast carcinomas and LAMA5 downregulation attenuates growth of human breast cancer cells. Prepubertal luminal deletion of Lama5 in MMTV-PyMT mice results in marked reduction in emergence of early hyperplasias, along with a shift towards luminal progenitor-like phenotype. However, single allele deletion, but not biallelic deletion of Lama5 inhibits growth and progression towards advanced mammary carcinomas. Lama5 deficient luminal epithelial cells collectively display widespread alterations in Fibroblast growth factor (Fgf) signalling genes, including increased expression of Fgf receptor 2 (Fgfr2). Inhibition of Fgf receptors decreases growth and induces apoptosis also in biallelic-Lama5-deleted organoids without affecting wildtype organoids. Our results demonstrate a critical role for the BM component LAMA5 in mammary tumour initiation and reveal mechanisms of ECM-epithelial interplay in breast tumour progression and phenotype maintenance.

cancer biology↗

bioRxiv2024

MatriCom: a scRNA-Seq data mining tool to infer ECM-ECM and cell-ECM communication systems

The ECM is a complex and dynamic meshwork of proteins that forms the framework of all multicellular organisms. Protein interactions within the ECM are critical to building and remodeling the ECM meshwork, while interactions between ECM proteins and cell surface receptors are essential for the initiation of signal transduction and the orchestration of cellular behaviors. Here, we report the development of MatriCom, a web application (https://matrinet.shinyapps.io/matricom) and a companion R package (https://github.com/Izzilab/MatriCom), devised to mine scRNA-Seq datasets and infer communications between ECM components and between different cell populations and the ECM. To impute interactions from expression data, MatriCom relies on a unique database, MatriComDB, that includes over 25,000 curated interactions involving matrisome components, with data on 80% of the [~]1,000 genes that compose the mammalian matrisome. MatriCom offers the option to query open-access datasets sourced from large sequencing efforts (Tabula Sapiens, The Human Protein Atlas, HuBMAP) or to process user-generated datasets. MatriCom is also tailored to account for the specific rules governing ECM protein interactions and offers options to customize the output through stringency filters. We illustrate the usability of MatriCom with the example of the human kidney matrisome communication network. Last, we demonstrate how the integration of 46 scRNA-Seq datasets led to the identification of both ubiquitous and tissue-specific ECM communication patterns. We envision that MatriCom will become a powerful resource to elucidate the roles of different cell populations in ECM-ECM and cell-ECM interactions and their dysregulations in the context of diseases such as cancer or fibrosis. ONE SENTENCE SUMMARYMatriCom is a web application devised to mine scRNA sequencing datasets to infer ECM-ECM and cell-ECM communication systems in the context of the diverse cell populations that constitute any tissue or organ.

systems biology↗

bioRxiv2024

ProToDeviseR: an automated protein topology scheme generator

MotivationAmino acid sequence characterization is a fundamental part of virtually any protein analysis, and creating concise and clear protein topology schemes is of high importance in proteomics studies. Although numerous databases and prediction servers exist, it is challenging to incorporate data from various, and sometimes contending, resources into a publication-ready scheme. ResultsHere, we present the Protein Topology Deviser R package (ProToDeviseR) for the automatic generation of protein topology schemes from database accession numbers, raw results from multiple prediction servers, or a manually prepared table of features. The application offers a graphical user interface, implemented in R Shiny, hosting an enhanced version of Pfams domains generator for the rendering of visually appealing schemes. Results show that ProToDeviseR can easily and quickly generate topology schemes by interrogating UniProt or NCBI GenPept databases and elegantly combine features from various resources. AvailabilitySource code (https://github.com/izzilab/protodeviser) is available under GPLv3 license; the tool is also accessible for online use (https://matrinet.shinyapps.io/protodeviser/), without the need of installation.

bioinformatics↗

bioRxiv2024

Mycolic acid and cholesterol induced transcriptomic adaptations in wild type and Mce complex ATPase subunit deleted strain of M. tuberculosis H37Rv

During infection and latency, Mycobacterium tuberculosis (Mtb) primarily relies on lipids as its main energy source. The Mtb mammalian cell entry (Mce) complexes function as lipid transporters with Mkl as the ATPase subunit for substrate translocation. Cholesterol and mycolic acid are essential to the infectiousness and pathogenicity of Mtb. Here, we have investigated the transcriptomic responses of wild type and{Delta} mkl strains of Mtb to cholesterol and mycolic acid through RNAseq analysis. The number of differentially expressed genes was always higher when grown on cholesterol than on mycolic acid. In most cases,{Delta} mkl showed the opposite gene expression pattern compared to the wild type. Among the four mce operons, significant changes in expression patterns were observed mainly in the genes of mce3 and mce4 operons. The upregulation of mce3 operon and the downregulation of mce4 operon in the presence of mycolic acid and cholesterol is intriguing. The transcriptome profile of genes involved in mycolic acid synthesis did not show significant change to either mycolic acid or cholesterol. However, interestingly, both mycolic acid and cholesterol induce upregulation of methyl citrate cycle and dormancy related genes indicating their significance during Mtb persistence and provides insights on Mtbs adaptive strategies under stress through transcriptional remodelling.

biochemistry↗

bioRxiv2023

Collagen prolyl 4-hydroxylases have sequence specificity towards different X-Pro-Gly triplets

Formation of 4-hydroxyproline (4Hyp) in -X-Pro-Gly- collagen sequences is essential for the thermal stability of collagen molecules. 4Hyp formation is catalyzed by collagen prolyl 4-hydroxylases (C- P4H). Here we identify specific roles for the two main C-P4H isoenzymes by 4Hyp analysis of type I and IV collagens. Loss of C-P4H-I mainly affected prolines preceded by an X-position amino acid with a positively charged or a polar uncharged side chain. In contrast, loss of C-P4H-II affected triplets with a negatively charged glutamate or aspartate in the X-position, and their hydroxylation was found to be important as loss of C-P4H-II alone resulted in reduced collagen melting temperature and altered assembly of collagen fibrils and basement membrane. The C-P4H isoenzyme differences in substrate specificity were explained by selective substrate binding to the active site resulting in differences in Km and Vmax values. In conclusion, this study provides a molecular level explanation for the need of multiple C-P4H isoenzymes to generate collagen molecules capable to assemble into intact extracellular matrix structures.

molecular biology↗

bioRxiv2023

Matrisome AnalyzeR: A suite of tools to annotate and quantify ECM molecules in big datasets across organisms

The extracellular matrix (ECM) is a complex meshwork of proteins that forms the scaffold of all tissues in multicellular organisms. It plays critical roles in all aspects of life: from orchestrating cell migration during development, to supporting tissue repair. It also plays critical roles in the etiology or progression of diseases. To study this compartment, we defined the compendium of all genes encoding ECM and ECM-associated proteins for multiple organisms. We termed this compendium the "matrisome" and further classified matrisome components into different structural or functional categories. This nomenclature is now largely adopted by the research community to annotate -omics datasets and has contributed to advance both fundamental and translational ECM research. Here, we report the development of Matrisome AnalyzeR, a suite of tools including a web-based application (https://sites.google.com/uic.edu/matrisome/tools/matrisome-analyzer) and an R package (https://github.com/Matrisome/MatrisomeAnalyzeR). The web application can be used by anyone interested in annotating, classifying, and tabulating matrisome molecules in large datasets without requiring programming knowledge. The companion R package is available to more experienced users, interested in processing larger datasets or in additional data visualization options. SUMMARY STATEMENTMatrisome AnalyzeR is a suite of tools, including a web-based app and an R package, designed to facilitate the annotation and quantification of extracellular matrix components in big datasets.

bioinformatics↗

bioRxiv2023

TGF-β induces matrisome pathological alterations and EMT in patient-derived prostate cancer tumoroids

Extracellular matrix (ECM) tumorigenic alterations resulting in high matrix deposition and stiffening are hallmarks of adenocarcinomas and are collectively defined as desmoplasia. Here, we thoroughly analysed primary prostate cancer tissues obtained from numerous patients undergoing radical prostatectomy to highlight reproducible structural changes in the ECM leading to the loss of the glandular architecture. Starting from patient cells, we established prostate cancer tumoroids (PCTs) and demonstrated they require TGF-{beta} signalling pathway activity to preserve phenotypical and structural similarities with the tissue of origin. By modulating TGF-{beta} signalling pathway in PCTs, we unveiled its role in ECM accumulation and remodelling in prostate cancer. We also found that TGF-{beta}-induced ECM remodelling is responsible for the initiation of prostate cell epithelial-to-mesenchymal transition (EMT) and the acquisition of a migratory, invasive phenotype. Our findings highlight the cooperative role of TGF-{beta} signalling and ECM desmoplasia in prompting prostate cell EMT and promoting tumour progression and dissemination

cancer biology↗

bioRxiv2022

Collagen XVIII promotes breast cancer through EGFR/ErbB signaling and its ablation improves the efficacy of ErbB-targeting inhibitors

The tumor extracellular matrix (ECM) is a critical regulator of cancer progression and metastasis, significantly affecting the treatment response. Expression of collagen XVIII (ColXVIII), a ubiquitous component of basement membranes, is induced in many solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII is markedly upregulated in human breast cancer (BC) cells and is closely associated with a poor prognosis in high-grade BC, especially in human epidermal growth factor receptor 2 (HER2)-positive and basal/triple-negative cases. We identified a novel mechanism of action for ColXVIII as a modulator of epidermal growth factor receptor (EGFR/ErbB) signaling and show that it forms a complex with EGFR, HER2 and 6 integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/Akt cascades. In vivo studies with Col18a1 mouse models crossed with the MMTV-PyMT mammary carcinogenesis model showed that the short ColXVIII isoform promotes BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in both mouse and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII in human BC cells and the MMTV-PyMT model substantially improved the efficacy of certain EGFR/ERbB-targeting therapies, even abolishing resistance to EGFR/ErbB inhibitors in some cell lines. In summary, a new function is revealed for ColXVIII in sustaining the stemness properties of BC cells, and tumor progression and metastasis through EGFR/ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have significant therapeutic potential. One Sentence SummaryCollagen XVIII is upregulated in breast cancer and promotes mammary carcinogenesis through EGFR/ErbB signaling and by sustaining cancer stem cells, so that its targeting improves the efficacy of ErbB-targeted therapies.

cancer biology↗

bioRxiv2021

Temporally and Spatially Regulated Collagen XVIII Isoforms Impact Ureteric Patterning Through Their TSP1-like Domain

Collagen XVIII (ColXVIII) is a component of the extracellular matrix implicated in embryogenesis and control of homeostasis. We provide evidence that ColXVIII has a specific role in kidney ontogenesis by regulating the interaction between mesenchymal and epithelial tissues as observed in analyses of total and isoform-specific knockout embryos, mice, and ex vivo organ primordia. ColXVIII deficiency, both temporally and spatially, impacts the 3D pattern of ureteric tree branching morphogenesis via its specific isoforms. Proper development of ureteric tree depends on a tight control of the nephron progenitor cells (NPCs). ColXVIII-deficient NPCs are leaving the NPC pool faster than in controls. Moreover, the data suggests that ColXVIII mediates the kidney epithelial tree patterning via its N-terminal domains, and especially the Thrombospondin-1-like domain, and that this morphogenetic effect involves ureteric epithelial integrins. Altogether, the results propose a significant role for ColXVIII in a complex signalling network regulating renal progenitors and kidney development.

developmental biology↗