Biology subjects

Varon, C.

Publications and source records attributed to Varon, C..

5 recordsLinked to original sources

bioRxiv2026

Cytolethal distending toxin promotes epithelial-to-mesenchymal transition by modulating AKT-Dependent β-catenin Ser552 phosphorylation

Bacterial genotoxins, Cytolethal Distending Toxin (CDT) and colibactin, cause DNA damage in intoxicated epithelial cells of the host. DNA damage influences {beta}-catenin signaling, altering its stability and nuclear translocation, potentially contributing to cancer development. Using non-transformed hepatocytes and cancer-derived intestinal and hepatic epithelial cell lines, we showed that CDT/CdtB induces the phosphorylation of {beta}-catenin at serine 552, along with the loss of {beta}-catenin from adherens junctions. This leads to the subsequent cytoplasmic accumulation and nuclear translocation of {beta}-catenin, ultimately driving TCF/LEF transcription, the crucial downstream event of Wnt/{beta}-catenin signaling, as well as the transcription of some {beta}-catenin target genes. Colibactin induces similar effects. MK-2206, a direct AKT inhibitor, and metformin, an AMP-activated protein kinase activator that indirectly inhibits AKT, both protected cells against various effects induced by CdtB exposure. These effects include {beta}-catenin phosphorylation at Ser552, the disassembly of cell-cell junctions and the subsequent nuclear accumulation of phosphorylated {beta}-catenin, leading to reduced TCF/LEF-mediated transcription. Additionally, MK-2206 and metformin protected from CdtB-induced epithelial-mesenchymal transition (EMT), including increased nuclear accumulation of SNAIL, enhanced matrix degradation and motility. Overall, these data show that infection with genotoxin-producing bacteria controls some EMT features through {beta}-catenin and AKT-dependent signaling.

cancer biology↗

bioRxiv2025

Wild-type and mutated beta-catenin differently repress RND3/RHOE expression in hepatocellular carcinoma

Background & AimsTumor development and progression are mainly driven by oncogenic mutations but are also regulated by physical factors, such as applied forces or microenvironment stiffness. Through its structural and transcriptional functions, {beta}catenin is a key factor that acts on both aspects to promote liver tumorigenesis, leading to hepatocellular carcinoma (HCC) development. However, the mechanisms by which these two functions regulate downstream targets remain poorly understood. Herein, we describe Rnd3, also called RhoE, an atypical member of the Rho GTPase family, as a common target of both functions of {beta}-catenin. We previously demonstrated that RND3 expression is downregulated in HCC, which correlates with intrahepatic metastasis. Yet, a molecular understanding of how Rnd3 expression is dysregulated in cancer is largely missing. Approach & ResultsUsing human HCC samples and cultured cell lines, we demonstrate that Rnd3 expression is regulated by {beta}-catenin pathways, regardless of their mutational status. Both the transcriptional and the structural activity of {beta}-catenin repress the expression of RND3. Indeed, we found that wild-type {beta}-catenin suppresses RND3 transcription through the Hippo pathway, whereas oncogenic {beta}-catenin downregulates RND3 expression through miRNA targeting its 3UTR. ConclusionRnd3 may constitute a key protein involved in the transcriptional program driven by oncogenic {beta}-catenin in HCC and as a mediator of the mechanosensitive response associated with cell-cell adhesion.

cancer biology↗

bioRxiv2025

Immunosuppressive myeloid cells induce mesenchymal-like breast cancer stem cells by a mechanism involving membrane-bound TGF-β1.

Suppressive myeloid cells play a central role in cancer escape from anti-tumor immunity. Beyond their immunosuppressive function, these cells are capable of exerting multiple other pro-tumoral activities, including the promotion of cancer cell survival, invasion and metastasis. The ability of some myeloid subsets to induce cancer stemness has recently emerged. Here we demonstrated that human immunosuppressive myeloid cells, generated in vitro or isolated from breast cancer patients, promoted the acquisition of mesenchymal-like breast cancer stemness properties. This cancer-stemness-inducing function was restricted to a myeloid subset expressing the glycoprotein CD52. Single cell transcriptomic- and surface proteome-based interactome analysis pointed towards membrane-bound TGF-{beta}1 as a potential factor involved in cancer stemness induction. Functional inhibition of the TGF-{beta}1 pathway blocked the emergence of cancer stem cells induced by suppressive myeloid cells. These results therefore identified the underlying mechanisms of a new tumor-promoting function of immunosuppressive myeloid cells, which may potentially be targeted. HighlightsO_LIImmunosuppressive CD33highCD52+ myeloid cells induce mesenchymal-like cancer stem cells C_LIO_LICancer stemness induction requires membrane bound TGF-{beta}1 C_LIO_LIBlockade of the TGF-{beta}1 pathway prevents cancer stemness induction C_LI

cancer biology↗

bioRxiv2022

The cytolethal distending toxin modulates cell differentiation and elicits epithelial to mesenchymal transition

We are frequently exposed to bacterial genotoxins, such as cytolethal distending toxin (CDT), a prevalent heterotrimeric toxin whose active moiety is its CdtB subunit. CdtB triggers potent DNA damage, predisposing factors in the development of cancers, in host cells. CDT from Helicobacter hepaticus, a mouse pathogen, was shown to be directly involved in the development of murine hepatocarcinoma. Preliminary studies have shown that CDT induces certain phenotypes reminiscent of epithelial to mesenchymal transition (EMT), a process by which cells lose their epithelial characteristics in favor of mesenchymal ones, conducive to cell motility. In the present study, we investigated the different steps of EMT using liver tissues of mice infected with H. hepaticus, as well as human epithelial cell lines and xenograft mouse models following H. hepaticus CdtB expression. Most of the different steps of the EMT process were reproduced throughout the studied models. Indeed, microarray data showed a CdtB- dependent regulation of EMT-related transcripts. The key transcriptional regulators of EMT (SNAIL1 and ZEB1) and EMT markers (Vimentin, Fibronectin and 5{beta}1 integrin) were upregulated both at RNA and protein levels in response to CdtB. It also induced cell-cell junctions disassembly, causing individualization of cells and acquisition of a spindle-like morphology. CdtB activated the expression and activity of matrix metalloproteases and increased cell motility. This study demonstrated that CDT/CdtB elicits EMT process activation, supporting the idea that infection with genotoxin-producing bacteria can promote malignant transformation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/487255v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@f94756org.highwire.dtl.DTLVardef@1ba7d59org.highwire.dtl.DTLVardef@7b80ccorg.highwire.dtl.DTLVardef@44d56d_HPS_FORMAT_FIGEXP M_FIG C_FIG Author SummaryWe are frequently exposed to infection with genotoxin--producing bacterial from the gut microbiota, such as cytolethal distending toxin (CDT). CDT, via its active CdtB subunit, causes severe DNA damage in host cells, well-known risk factor of cancer development and progression. Chronic infection with CDT-producing bacteria is thus involved in cancer development. CDT is widespread among many bacteria and its impact in human cancer seems likely underestimated. Despite its major significance, CDT remains little studied. Here, we showed that cells exposed to CdtB are no longer cohesive, become individualized and acquire a spindle-shaped morphology known to be conducive to migration. These cells also express increased level of mesenchymal markers, as well as increased level of SNAIL1 and ZEB1, two key transcription factors orchestrating a crucial mechanism for cancer initiation and progression: epithelial to mesenchymal transition. These effects induced by CdtB were associated with increased matrix metalloproteinases degrading activity and emergence of cellular motility. Collectively, these data showed that CdB activates epithelial to mesenchymal transition, supporting the role of CDT in tumorigenesis.

microbiology↗

bioRxiv2019

R-DECO: An open-source Matlab based graphical user interface for the detection and correction of R-peaks

Many of the existing ECG toolboxes focus on the derivation of heart rate variability features from RR-intervals. By doing so, they assume correct detection of the QRS-complexes. However, it is highly likely that not all detections are correct. Therefore, it is recommended to visualize the actual R-peak positions in the ECG signal and allow manual adaptations. In this paper we present R-DECO, an easy-to-use graphical user interface for the detection and correction of R-peaks. Within R-DECO, the R-peaks are detected by an adaptation of the Pan-Tompkins algorithm. Instead of using all the pre-processing steps of the latter algorithm, the proposed algorithm uses only an envelope-based procedure to flatten the ECG and enhance the QRS-complexes. The algorithm obtained an overall sensitivity of 99.60% and PPV of 99.69% on the MIT/BIH arrhythmia database. Additionally, R-DECO includes support for several input data formats for ECG signals, three basic filters, the possibility to load other R-peak locations and intuitive methods to correct ectopic, wrong, or missed heartbeats. All functionalities can be accessed via the graphical user interface and the analysis results can be exported as Matlab or Excel files. The software is publicly available. Through its easy-to-use-graphical user interface, R-DECO allows both clinicians and researchers to use all functionalities, without previous knowledge.

bioengineering↗