Biology subjects

Lafanechere, L.

Publications and source records attributed to Lafanechere, L..

4 recordsLinked to original sources

bioRxiv2026

Winding-Up of Fibrin Fibers as a Novel Mechanism of Platelet-Mediated Fiber Compaction

This study reveals a previously unrecognized mechanism by which platelets retract and compact fibrin fibers. Using a newly developed 2D fiber-retraction assay, we observed an initial "gearwheel" pattern of actin-myosin organization in spread platelets with associated, extracellular fibrin patches that appear to form an initiation complex for fibrin fiber attachment and rearrangement. The final outcome of this process results in two morphologically different platelet populations. Spread platelets with coiled fibers around and above their pseudo-nucleus. Other platelets are only partially spread on the glass surface and are surrounded by tightly packed fibrin fibers around bulbous protrusions ("bulbs"), mirroring the architecture of platelets and adjacent fibers within a retracted clot. Thus, the observed compaction process might also take place during clot retraction in order to reduce clot volume, stiffen the clot and enhance wound repair. Apart from pulling on fibers like on a rope, platelets actively wrap fibrin fibers into compact structures, similar to balls of wool. Besides DNA packaging, this represents a new example of a natural fiber compaction mechanism. Using a combination of 3D clot-retraction and 2D fiber-retraction assays, expansion and electron microscopy, live imaging and mathematical modeling, we show that platelets use an actomyosin-driven motion to gather and loop fibrin fibers around the base of bulbous protrusions. These bulbs form when a platelet becomes trapped between fibrin fibers during 3D clot retraction or 2D fiber-retraction assays. These findings complement and extend earlier models of platelet-mediated fibrin fiber retractions, offering new insight into how platelets mechanically organize fibrin fibers.

cell biology↗

bioRxiv2025

Preventing neuropathy and improving anti-cancer chemotherapy with a carbazole-based compound

Advances in cancer treatment have led to a steady increase in the rate of disease remission. However, while many treatment-related adverse effects gradually resolve after therapy, chemotherapy-induced peripheral neuropathy (CIPN) often persists, with no means of prevention or direct treatment available. Herein, we present Carba1, a novel bi-functional carbazole that mitigates neuropathy through two distinct mechanisms. First, by interacting with tubulin, Carba1 reduces the required dose of taxanes, widely used chemotherapy drugs notorious for their toxic side effects, including CIPN. Second, Carba1 activates nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, triggering a metabolic rewiring that enhances the resilience of neurons and Schwann cells against chemotherapy-induced toxicity. We demonstrate the neuroprotective efficacy of Carba1 both in vitro, against neurotoxicity induced by paclitaxel (PTX), cisplatin, and bortezomib, and in vivo in a rat model of PTX-induced neuropathy. Importantly, we establish that Carba1 does not compromise the therapeutic efficacy of PTX nor promotes tumor growth. Comparative analyses of Carba1 derivatives further suggest the potential of designing compounds with either dual synergistic and neuroprotective activity or exclusive neuroprotective properties. Altogether, our findings position Carba1 as a promising therapeutic candidate for preventing CIPN, with the potential, if successfully translated to clinical settings, to improve both the quality of life and treatment outcome for cancer patients.

cancer biology↗

bioRxiv2023

Focal adhesions are controlled by microtubules through local contractility regulation

Microtubules regulate cell polarity and migration by local activation of focal adhesion turnover, but the mechanism of this process is insufficiently understood. Molecular complexes containing KANK family proteins connect microtubules with the major component of focal adhesions, talin. Local optogenetic activation of KANK1-mediated links which promoted microtubule targeting to individual focal adhesion resulting in its centripetal sliding and rapid disassembly. The sliding is preceded by a local increase of traction force due to accumulation of myosin-II and actin in the proximity of the focal adhesion. Knockdown of Rho activator GEF-H1 prevented development of traction force and abolished sliding and disassembly of focal adhesion upon KANK activation. Other players participating in microtubule-driven KANK-dependent focal adhesion disassembly include kinases ROCK and PAK, as well as microtubules/focal adhesions associated proteins Kinesin-1, APC and TAT. Finally, we propose a physical model of a microtubule-driven focal adhesion disruption involving local GEF-H1/RhoA/ROCK dependent activation of contractility which is consistent with experimental data.

cell biology↗

bioRxiv2020

Two antagonistic microtubule targeting drugs act synergistically to kill cancer cells

Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for drugs which could potentiate its therapeutic effect. We have screened a chemical library and selected Carba1, a carbazolone, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. The Carba1-induced modulation of microtubule dynamics increases the accumulation of fluorescent paclitaxel inside microtubules, providing a mechanistic explanation of the observed synergy between Carba1 and paclitaxel. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel accumulation in microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

cancer biology↗