Our research axes

This research axis aims to elucidate how cytoskeletal dynamics regulate fundamental cellular functions and to identify new pharmacological targets with strong translational potential. It relies on chemobiology approaches combining the development of specific cellular assays, chemical library screening, and molecular target identification.

These efforts led to the identification of a novel carbazole compound, Carba1, which displays two distinct pharmacological activities. Carba1 targets tubulin and synergizes with taxanes, allowing dose reduction of these potent but toxic anticancer agents while preserving therapeutic efficacy. In addition, Carba1 activates NAMPT, a key metabolic enzyme, thereby providing neuroprotection against chemotherapy-induced neuropathy (Bosc et al., 2025). Our team is currently developing non-invasive biomarkers of Carba1 therapeutic efficacy. The start-up Saxol, co-founded by L. Lafanechère, is now responsible for regulatory preclinical development with the goal of initiating a first-in-human clinical trial. Carba1 could thus become the first preventive treatment for chemotherapy-induced neuropathy.

In parallel, we are developing an innovative multidisciplinary strategy based on targeted degradation of key microtubule cytoskeleton proteins, in collaboration with the teams of A. Hamze (BioCis, Paris-Saclay) and M.J. Moutin (Grenoble Institute of Neurosciences). This project is structured around two distinct but complementary axes: (i) the development of PROTACs inducing targeted degradation of tubulin for cancer therapy; and (ii) the development of PROTACs targeting the detyrosinases VASHs/SVBP, key enzymes of the tubulin detyrosination cycle, which is involved in both cardiomyopathies through altered mechanotransduction and tumor progression.

Key references:

Bosc L., Pero M.E., Balayssac D., Jacquemot D., Allard J., Suzanne P., Vollaire J., Cottet-Rousselle C., Michallet S., Villaret J., Torch S., Marais S., Elena-Herrmann B., Schlattner U., Mercier A., Josserand V., Thibert C., Dallemagne P., Bartolini F., Lafanechère L. Preventing neuropathy and improving anti-cancer chemotherapy with a carbazole-based compound. Science Advances, 2025.

Mercier A.E., Joubert A.M., Prudent R., Viallet J., Desroches-Castan A., De Koning L., Mabeta P., Helena J., Pepper M.S., Lafanechère L. Sulfamoylated Estradiol Analogs Targeting the Actin and Microtubule Cytoskeletons Demonstrate Anti-Cancer Properties In Vitro and In Ovo. Cancers (Basel), 2024.

Nolte E.M., Joubert A.M., Lafanechère L., Mercier A.E. Radiosensitization of breast cancer cells with a 2-methoxyestradiol analogue affects DNA damage and repair signaling in vitro. Int J Mol Sci, 2023.

Lafanechère L. The microtubule cytoskeleton: an old validated target for novel therapeutic drugs. Front Pharmacol, 2022.

Ribba A.S., Fraboulet S., Sadoul K., Lafanechère L. The Role of LIM Kinases during Development: A Lens to Get a Glimpse of Their Implication in Pathologies. Cells, 2022.

Laisne M.C., Michallet S., Lafanechère L. Characterization of Microtubule Destabilizing Drugs: A Quantitative Cell-Based Assay That Bridges the Gap between Tubulin-Based and Cytotoxicity Assays. Cancers, 2021.

Peronne L., Denarier E., Rai A., Prudent R., Vernet A., Suzanne P., Ramirez-Rios S., Michallet S., Guidetti M., Vollaire J., Lucena-Agell D., Ribba A-S., Josserand V., Coll J-L., Dallemagne P., Díaz J.F., Oliva M., Sadoul K., Akhmanova A., Andrieux A., Lafanechère L. Two antagonistic microtubule targeting drugs act synergistically to kill cancer cells. Cancers, 2020.

Ramirez-Rios S., Michallet S., Peris L., Barette C., Rabat C., Feng Y., Fauvarque M.O., Andrieux A., Sadoul K., Lafanechère L. A new quantitative cell-based assay reveals unexpected microtubule stabilizing activity of certain kinase inhibitors, clinically approved or in the process of approval. Front Pharmacol, 2020.

This research axis investigates how mechanical constraints imposed by the microenvironment—such as compression, tissue curvature, and variations in tension—are integrated by epithelial cells to maintain tissue homeostasis. It is rooted in a mechanobiology approach that links the physical properties of tissues to cellular and nuclear responses.

Work carried out within the team has shown that epithelial deformations trigger specific collective responses, including calcium waves, changes in nuclear tension, and transcriptional remodeling. These observations have led the team to focus on the nucleolus as a central target of mechanical signals, given its key role in regulating ribosome biogenesis, cell-cycle progression, and cellular stress responses.

By combining biophysics, cell biology, micro-engineering, and molecular analyses, this axis aims to decipher the mechanotransduction pathways that link mechanical constraints to nuclear and nucleolar responses, and to understand how these mechanisms contribute to the regulation of epithelial homeostasis in physiological and pathological contexts, particularly in conditions of increased tissue density and cancer.

Key references:

Shetty Y., Dolega M.E. Mechanobiology of the nucleolus. Biology of the Cell, 2026 (accepté).

Brun-Cosme-Bruny M., Pernet L., Elias K., Guilluy C., Oddou C., Dolega M.E. Mechanical stress dissipation in locally folded epithelia is orchestrated by calcium waves and nuclear tension changes. iScience, 2025.

Blonski S., Aureille J., Badawi S., Pernet L., Fraboulet S., Korczyk P., Recho P., Guilluy C.*, Dolega M.E.*. Direction of epithelial folding defines impact of mechanical forces on epithelial state. Developmental Cell, 2021.

Dolega M.E., Monnier S., Brunel B., Joanny J.F., Recho P., Cappello G. Extracellular matrix in cell aggregates is a proxy to mechanically control cell proliferation and motility. eLife, 2021.

Aureille J., Pezet M., Pernet L., Mazzega J., Grichine A., Guilluy C.*, Dolega M.E.*. Cell fluorescence photo-activation as a method to study cellular sub-populations in mechanically heterogeneous environments. Molecular Biology of the Cell, 2021.

Dolega M.E.*, Delarue M., Ingremeau F., Prost J., Delon A., Cappello G.*. Cell-like pressure sensors reveal increase of mechanical stress towards the core of multicellular spheroids under compression. Nature Communications, 2017.

In line with the scientific trajectory defined in the HCERES evaluation, the current organization will evolve toward the creation of a new team, entitled MechaCell – Epithelial homeostasis, mechano-adaptation and cell fate. The team will be co-led by M. Dolega and C. Tomba and will build on the convergence of the two current scientific axes around a common program focused on the role of the mechanical environment—particularly compression and tissue curvature—in the regulation of epithelial homeostasis and cell fate, while ensuring continuity of expertise and resources developed within the present team.