Biology subjects

Oddou, C.

Publications and source records attributed to Oddou, C..

7 recordsLinked to original sources

bioRxiv2026

Letting go to hold on: loss of CCM2 disrupts endothelial force balance in cerebral cavernous malformations

Cerebral cavernous malformations (CCM) are vascular lesions characterized by impaired endothelial integrity and altered cell-cell and cell-matrix interactions. While endothelial contractility and tractions have been implicated in CCM, how these forces are transmitted and coordinated across adhesion systems remains unknown. Here, we combined genetically encoded FRET-based molecular tension sensors of vinculin and VE-cadherin with quantitative analysis of adhesion organization to dissect this force balance in CCM2-deficient endothelial monolayers. We found that CCM2 loss redistributes molecular forces, partially through ROCK-dependent contractility, across endothelial adhesions, shifting mechanical engagement from cell-cell junctions toward the cell-matrix interface. Matrix stiffness further amplifies this imbalance, as healthy endothelial cells maintain the balance between cell-cell and cell-matrix adhesions by reinforcing both in response to stiffening, whereas CCM2-deficient cells preferentially reinforce the cell-matrix interface. These findings suggest that CCM-associated matrix remodeling could reinforce an already altered mechanical state, establishing a potential feed-forward interaction between endothelial force transmission and the extracellular environment. More broadly, our results identify the CCM complex as a molecular hub controlling force balance in response to the cell mechanical environment and establish a combined tension sensing and morphology-based imaging platform for studying adhesion mechanobiology.

biophysics↗

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↗

bioRxiv2026

The nucleolus is a mechanosensitive condensate that adapts ribosome biogenesis to mechanical forces

Intracellular compartmentalization is fundamental to cellular organization, yet mechanobiology has been largely understood through membrane-delimited structures and associated signaling pathways. Whether mechanical forces directly regulate biomolecular condensates, which organize many core cellular functions, remains largely unknown. This question is particularly relevant for the nucleolus, a prominent nuclear condensate that coordinates ribosome biogenesis and is known to remodel in response to diverse biochemical perturbations, placing it at the interface between cellular state and biosynthetic control. Here, we show that mechanical compression remodels nucleolar organization and reduces (ribosomal DNA) rDNA transcription, and identify nucleolin as a key mediator of this adaptive response. Compression induces rapid and reversible redistribution of nucleolin from the nucleolus to the nucleoplasm, accompanied by reduced occupancy at rDNA promoter regions and changes in rDNA transcription and precursor rRNA processing. The nucleolar response occurs independently of classical post-translational regulation of nucleolin and instead depends on the rate of nuclear deformation, with nucleolar organization and function scaling with nuclear volume loss, supporting a mechanism of biophysical regulation. Together, our findings establish the nucleolus as a mechanosensitive condensate and reveal dual regulation of ribosome biogenesis by mechanical compression, through rapid nucleolin-based biophysical adaptation followed by slower epigenetic remodeling.

cell biology↗

bioRxiv2025

Optogenetic SH3 nanoclustering of SRC and HCK uncovers the functional specificity of these redundant kinases in macrophages.

Understanding redundancy among Src Family Kinases (SFKs) challenges how cells achieve signaling specificity using closely related enzymes, and paves the way to revisit a basic property of any cell signaling network. Optogenetic control of the adaptor properties of the most redundant SFK members, SRC and HCK, was used to examine their potential specificity in macrophages. Uncoupling their kinase and adaptor functions uncovers an unique mechanism driven by oligomerized- and SH3-dependent specific binding that enables inducing distinct signaling outputs for each kinase. OptoSRC and optoHCK probes revealed that SRC and HCK can trigger specific cellular responses, despite only supposed overlapping functions. The specificity of optoHCK even unveils a novel role in activating polarized clathrin hotspots essential for directional migration. Redundancy could be rebuilt within optoHCK through stepwise optogenetic reconstruction of adaptor modules revealing the essential role of both membrane anchoring and SH2-domain. This deconstructive approach of SFK activation elucidated the molecular basis of their shared and unique signaling activities and supports a model of cooperative functional entanglement between SFK members, rather than simple redundancy.

cell biology↗

bioRxiv2025

Mechanical Stress dissipation in locally folded epithelia is orchestrated by calcium waves and nuclear tension changes

Epithelia are continuously exposed to a range of biomechanical forces such as compression, stretch and shear stress arising from their dynamic microenvironments and associated to their function. Changes in tension such as stretch are known to trigger cell rearrangements and divisions, and impact cellular transcription until mechanical stress is dissipated. How cells process, adapt and respond to mechanical stress is being intensively investigated. In here we focus on epithelial folding which is the fundamental process of transformation of flatmonolayers into 3D functional tissues. By combining the innovative method for fold generation, live imaging, mechanobiology tools and chemical screening, we uncover the role of calcium waves on mechanical adaptation of folded epithelia that occurs at the tissue and nuclear level. Folding associated tensional load results in the nuclear flattening which is recovered in the time scale of minutes and is dependent on the calcium wave that spread outwards from the channel and across the epithelium. By creating a mutant overexpressing LBR that relaxed nuclear envelope, we demonstrated that despite presence of calcium waves, nuclear tension increase was essential to trigger nuclear shape recovery post folding through the activation of cellular contractility in the cPLA2 dependent manner. Overall our results identify the molecular mechanism for nuclear shape recovery and indicate that mechanical stress dissipation program is activated at the level of nuclei which serve as internal tension sensors.

developmental biology↗

bioRxiv2023

An optogenetic approach to control and monitor inflammasome activation.

Inflammasomes are multiprotein platforms which control caspase-1 activation, leading to the processing of proinflammatory cytokines into mature and active cytokines IL-1{beta} and IL-18, and to pyroptosis through the cleavage of gasdermin-D (GSDMD). Inflammasomes assemble upon activation of specific cytosolic pattern recognition receptors (PRRs) by damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). They converge to the nucleation of apoptosis-associated speck-like containing a caspase activation and recruitment domain (ASC) to form hetero-oligomers with caspase-1. Studying inflammasome encoding activities remains challenging because PAMPs and DAMPs are sensed by a large diversity of cytosolic and membranous PRRs. To bypass the different signals required to activate the inflammasome, we designed an optogenetic approach to temporally and quantitatively manipulate ASC assembly (i.e. in a PAMP- or DAMP-independent manner). We reveal that controlling light-sensitive oligomerization of ASC is sufficient to recapitulate the classical features of inflammasomes within minutes, and enabled us to decipher the complexity of volume regulation and pore opening during pyroptosis. Overall, this approach offers interesting perspective to decipher PRR signaling pathways in the field of innate immunity.

immunology↗

bioRxiv2019

Molecular flux control encodes distinct cytoskeletal responses by specifying SRC signaling pathway usage.

Multi-domain signaling proteins sample numerous stimuli to coordinate distinct cellular responses. Understanding the mechanisms of their pleiotropic signaling activity requires to directly manipulate their activity of decision leading to distinct cellular responses. We developed an optogenetic probe, optoSRC, to control spatio-temporally the SRC kinase, a representative example of versatile signaling node, and challenge its ability to generate different cellular responses. Genesis of different local molecular fluxes of the same optoSRC to adhesion sites, was sufficient to trigger distinct and specific acto-adhesive responses. Collectively, this study reveals how hijacking the pleiotropy of SRC signaling by modulating in space and time subcellular molecular fluxes of active SRC kinases.

cell biology↗