Biology subjects

SALTEL, F.

Publications and source records attributed to SALTEL, F..

6 recordsLinked to original sources

bioRxiv2025

p190A/ARHGAP35 and p190B/ARHGAP5 proteins in endometrial cancer, a novel cancer-relevant paralog interplay

Endometrial cancer is one of the main gynecological malignancies worldwide, with an estimated 320, 000 new cases annually. Several studies highlight ARHGAP35 as a significantly mutated gene in these tumors. It encodes for the protein p190RhoGAP-A (p190A), which is a major regulator of the small GTPase family of proteins. ARHGAP5 is a paralog of ARHGAP35 that encodes the protein p190RhoGAP-B (p190B). By analyzing human endometrial cancer samples, we found a co-occurrence of mutations in ARHGAP35 and ARHGAP5 genes and we reported that both are less expressed at the mRNA level in tumoral samples compared to healthy tissues. We were interested in understanding the impact of p190A/B under-expression in endometrial cancer and the relationship between the two paralogs. To do so, we have used CRISPR/Cas9 technology to generate HEC-1-A knockout cells for p190A and p190B. We showed that removal of each paralog led to a similar actin remodeling phenotype with the formation of Cross-Linked Actin Networks (CLANs), dependent on the Rho/ROCK pathway. Moreover, proteomic analysis of p190A and p190B knockout cells highlighted similar affected cell functions. Finally, our study demonstrates a synthetic lethality between p190A and p190B where removal of both paralogs is deleterious in endometrial cancer cells, unveiling a potential actionable vulnerability.

cancer biology↗

bioRxiv2025

Cancer cells transfer invasive properties through microRNAs contained in collagen-tracks

Invasion is a prerequisite for metastasis formation. During tumor development, the extracellular matrix (ECM) is remodeled in part through overexpression of type I collagen, increasing tumor microenvironment stiffness, and facilitating cancer dissemination. During breast cancer cell migration, we observed membrane debris left behind, attached to the collagen fibrils, along the migration path. We named these structures collagen-tracks. These collagen-tracks can be deposited in 3D matrices in vitro and in vivo and their formation is stimulated by the interaction between the ECM and matrix receptors, such as the discoidin-domain receptor (DDR1). However, they are different from structures already known to be involved in cell-cell communication such as exosomes and migrasomes, due to their specific nucleic acid and protein contents. When deposited by highly invasive breast cancer cells, internalized collagen-tracks reprogram non-invasive cells into highly pro-metastatic ones by inducing a partial epithelial-mesenchymal transition (EMT). This cell reprogramming is dependent on specific miRNAs present in the collagen-tracks, that are necessary to promote ECM degradation, increase cell motility and invasiveness. Collagen-tracks thus represent a new form of cell-cell communication important for driving tumor invasion that could be targeted to prevent metastasis.

cell biology↗

bioRxiv2024

Tks5 interactome reveals ER-associated machinery translation in invadosomes.

The ability to progress and invade through the extracellular matrix is a characteristic shared by both normal and cancer cells through the formation of structures called invadosomes gathering invadopodia and podosomes. These invadosomes are plastic and dynamic structures that can adopt different organizations depending on the cell types and the environment such as rosettes, dots or linear invadosomes. In this study, we used the specific invadosome marker Tks5 (SH3PXD2A), to identify common features in these different organizations. Tks5 immunoprecipitation coupled with mass spectrometry analysis allowed us to identify common proteins in these different models. We identified elements of the translation machinery, in particular the EIF4B protein, but also endoplasmic reticulum (ER) proteins as part of the invadosome structure. Providing new data on invadosome molecular composition through Tks5 interactome, we identified that ER-associated translation machinery is recruited to invadosome and involved in their formation, persistence and function in all types of invadosomes. SummaryInvadosomes are invasive F-actin structures exhibiting different organizations that degrade the extracellular matrix. The study uses their universal marker, Tks5, to provide new data about invadosome molecular composition and reveal the role of ER-associated translation machinery in invadosome formation and function.

cancer biology↗

bioRxiv2024

Identification of early-stage liver fibrosis by modifications in the interstitial space diffusive microenvironment using fluorescent single-walled carbon nanotubes

During liver fibrosis, recurrent hepatic injuries lead to accumulation of collagen and other extracellular matrix components in the interstitial space, ultimately disrupting liver functions. Early stages of liver fibrosis may be reversible, but opportunities for diagnosis at these stages are currently limited. Here, we show that the alterations of the interstitial space associated with fibrosis can be probed by tracking individual fluorescent single-walled carbon nanotubes (SWCNTs) diffusing in that space. In a mouse model of early liver fibrosis, we find that nanotubes generally explore elongated areas, whose length decrease as the disease progresses even in regions where histopathological examination does not reveal fibrosis yet. Furthermore, this decrease in nanotube mobility is a purely geometrical effect, as the instantaneous nanotube diffusivity stays unmodified. This work establishes the promise of SWCNTs both for the diagnosis of liver fibrosis at an early stage, and for more in-depth studies of the biophysical effects of the disease.

cancer biology↗

bioRxiv2021

The beta-catenin-target Fascin-1, altering hepatocyte differentiation, is a new marker of immature cells in hepatoblastomas

BACKGROUND & AIMS{beta}-catenin is a well-known effector of the Wnt pathway and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of {beta}-catenin are highly frequent in pediatric liver primary tumors. Those mutations are mostly heterozygous allowing the co-expression of wild-type (WT) and mutated {beta}-catenins in tumor cells. We investigated the interplay between WT and mutated {beta}-catenins in liver tumor cells, and searched for new actors of the {beta}-catenin pathway. METHODSUsing an RNAi strategy in {beta}-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of {beta}-catenin, carried mainly by, respectively, WT and mutated proteins. Their impact was characterized using transcriptomic and functional analyses. We studied mice that develop liver tumors upon activation of {beta}-catenin in hepatocytes (APCKO and {beta}-catenin{Delta}exon3 mice). We made use of transcriptomic data from mouse and human HB specimens and analyzed samples by immunohistochemistry. RESULTSWe highlighted an antagonist role of WT and mutated {beta}-catenins on hepatocyte differentiation as attested by alteration of hepatocyte markers expression and bile canaliculi formation. We characterized Fascin-1 as a target of {beta}-catenin involved in hepatocyte differentiation. Using mouse models that allow the formation of two phenotypically distinct tumors (differentiated or undifferentiated), we found that Fascin-1 expression is higher in undifferentiated tumors. Finally, we found that Fascin-1 is a specific marker of the embryonal component in human HBs. CONCLUSIONSIn mice and human, Fascin-1 expression is linked to loss of differentiation and polarity of hepatocytes. Thus, we highlighted Fascin-1 as a new player in the modulation of hepatocyte differentiation associated to {beta}-catenin pathway alteration in the liver. Data Transparency Statementstudy materials will be made available to other researchers upon request.

cancer biology↗

bioRxiv2020

DDR2 induces linear invadosome to promote angiogenesis in a fibrillar type I collagen context

To generate new vessels, endothelial cells (ECs) form invadosomes, which are actin-based microdomains with a proteolytic activity that degrade the basement membrane. We previously demonstrated that ECs form linear invadosomes in fibrillar type I collagen context. In this study, we aim to investigate the molecular mechanisms by which ECs guides angiogenesis in a fibrillar type I collagen context. We found that Discoidin Domain Receptor 2 (DDR2) is the collagen receptor tyrosine kinase required to form linear invadosomes in ECs. We further demonstrated that it acts in synergy with VEGF to promote extracellular matrix degradation. We highlighted the involvement of an interaction between DDR2 and the matrix metalloproteinase MMP14 in this process. Finally, using in vitro and ex-vivo angiogenesis assays, we demonstrated a pro-angiogenic function of DDR2 in a collagen-rich microenvironment. This study allows us to propose DDR2-dependent linear invadosomes as targets to modulate angiogenesis.

cell biology↗