Biology subjects

Leverrier-Penna, S.

Publications and source records attributed to Leverrier-Penna, S..

3 recordsLinked to original sources

bioRxiv2026

Endothelial gain of PIEZO/TRPV mechanosensors drives cavernous malformations

Vascular disease often begins as a failure to read mechanical force. Cerebral cavernous malformations (CCMs) are leaky, brain-invading capillary clusters that cause stroke and seizures and arise from endothelial loss of the CCM complex. They form exclusively in low-flow vessels but existing models cannot explain this selectivity. We previously established that CCM-mutant endothelium inverts its adhesive balance, weakening cell-cell junctions while building matrix-degrading adhesions. The mechanosensors imposing this switch are unknown. Here we show that the mechanosensitive Ca2+ channels PIEZO1, TRPV2 and TRPV4 are overexpressed in the endothelium of CCM lesions in a 42-patient cohort, and that lesion volume scales with their expression level. Mechanistically, PIEZO1 partners with TRPV4 to destabilise cell-cell junctions and with TRPV2 to reinforce cell-matrix adhesions; silencing TRPV4 restores junctional integrity and abolishes KLF4 induction, whereas silencing TRPV2 or inhibition with tranilast abolishes matrix degradation and invasion. In vivo, trpv4 knockdown or inhibition with GSK2798745 restores atrioventricular canal morphogenesis in ccm2-mutant zebrafish. Gain of mechanosensory channel function is thus a causal step in CCM pathogenesis, upstream of the KLF program. Combined therapeutic targeting of TRPV2 and TRPV4 with inhibitors validated in humans offers a route to therapy.

cell biology↗

bioRxiv2024

Oncogenic GNAQ/11-induced remodeling of the IP3/Calcium signaling pathway protects Uveal Melanoma against Calcium-driven cell death

Despite being considered a rare tumor, uveal melanoma (UVM) is the most common adult intraocular malignancy. With a poor prognosis and limited treatment options, up to 50% of patients develop metastases, primarily in the liver. A range of mutations and chromosomal aberrations with significant prognostic value has been associated with UVM pathogenesis. The most frequently mutated genes are GNAQ and GNA11, which encode the subunits of Gq proteins and are described as driver mutations that activate multiple signaling cascades involved in cell growth and proliferation. Directly downstream of Gq/11 activation, PLC{beta} engagement leads to sustained production of DAG and IP3. While the DAG/PKC/RasGRP3/MAPK signaling branch has been identified as an essential component of UVM unregulated proliferation, the role of IP3-mediated signals has been largely overlooked. Here, we demonstrate that, whilst maintaining Ca{superscript 2} homeostasis, UVM cells have developed a decoupling mechanism between IP3 and ER Ca{superscript 2} release by altering IP3 receptor (IP3R) expression. This correlation was observed in human UVM tumors, where IP3Rs were found to be downregulated. Critically, when IP3R3 expression was restored, UVM cells exhibited an increased tendency to undergo spontaneous cell death and became more sensitive to pro-apoptotic modulators of IP3R-mediated Ca{superscript 2} signaling, such as staurosporine and the Bcl2-IP3R disrupter peptide BIRD2. Finally, inhibition of the Gq/11 signaling pathway revealed that IP3R expression is negatively regulated by GNAQ/11 oncogenic activation. Hence, we demonstrated that by remodeling IP3R expression, GNAQ/11 oncogenes protect UVM cells against IP3-triggered Ca{superscript 2} overload and cell death. Therefore, the GNAQ/11 pathway not only drives proliferation through DAG activity but also provides a protective mechanism to evade IP3/Ca{superscript 2}-mediated cell death. These dual functions could potentially be exploited in novel combinatorial therapeutic strategies to effectively block UVM cell proliferation while simultaneously sensitizing them to cell death.

cancer biology↗

bioRxiv2021

The mechanosensitive TRPV2 calcium channel controls melanoma invasiveness and metastatic potential.

Discovery of therapeutic targets against metastasis is of primary importance since being the main cause of cancer-related death. Melanoma is a highly aggressive cancer endowed with a unique capacity of rapidly metastasizing. Deregulation of calcium homeostasis has been involved in numerous cellular metastatic behaviors, although the molecular determinants supporting these processes often remain unclear. Here, we evidenced a prominent expression of the plasma membrane TRPV2 calcium channel as a distinctive feature of melanoma tumors, directly related to melanoma metastatic progression and dissemination. In vitro as well as in vivo, TRPV2 activity was sufficient to confer both migratory and invasive phenotypes to non-invasive melanoma cells, while conversely upon TRPV2 silencing, highly metastatic melanoma cells failed to retain their malignant behaviors. We established a model whereupon activation of the mechanosensitive TRPV2 channel, localized in highly dynamic nascent adhesion clusters, directly regulates calpain-dependent cleavage of the adhesive protein talin together with F-actin network. By operating at the crossroad of the tumor microenvironment and the intracellular machinery, mechanosensitive TRPV2 channel controls melanoma cells aggressiveness. Finally in human melanoma tumor samples, TRPV2 overexpression represents a molecular marker of advanced malignancy and bad prognosis, highlighting a new therapeutic option for migrastatics in the treatment of metastatic melanoma. SignificanceOne essential feature of metastatic cells is enhanced motility and invasiveness. This study evidences TRPV2 channel control over metastatic melanoma invasiveness, highlights new migration regulatory mechanisms, and reveals this channel as a biomarker and migrastatic target for the treatment of advanced melanoma.

cancer biology↗