Maxime Lehmann

Université de Strasbourg

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Monique Dontenwill

Centre National de la Recherche Scientifique

Jacques Marvaldi

Aix-Marseille Université

Laurence Choulier

Laboratoire de Biophotonique et Pharmacologie

Sophie Martin

Institut de Cancérologie Strasbourg

Elisabete Cruz Da Silva

Université de Strasbourg

Isabelle Lelong-Rebel

Université de Strasbourg

Anne-Florence Blandin

Dana-Farber Cancer Institute

Fanny Noulet

Hôpital Beau-Séjour

José Luis

Centre National de la Recherche Scientifique

Véronique Rigot

Inserm

Cooperative Institutions

Centre National de la Recherche Scientifique

141

Inserm

Université de Strasbourg

Aix-Marseille Université

Laboratoire de Biophotonique et Pharmacologie

Institut de Neurobiologie de la Méditerranée

Mécanismes de Tumorigenèse et Thérapies Ciblées

Centre de Recherche en Cancérologie de Marseille

Institut de génétique et de biologie moléculaire et cellulaire

Laboratoire de Chimie Bactérienne

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Convergent effects of growth factors, hormones, and fibronectin are necessary for the enterocyte differentiation of a colon adenocarcinoma cell line (HT29-D4)

Differentiation (1998)

J. B. Rognoni Véronique Pichard Stéphane Honore Véronique Rigot Maxime Lehmann

Vinculin

Enterocyte

10.1007/s002580050255

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Citations (0)

Convergent effects of growth factors, hormones, and fibronectin are necessary for the enterocyte differentiation of a colon adenocarcinoma cell line (HT29-D4)

Differentiation (1998)

J. B. Rognoni Véronique Pichard Stéphane Honore Véronique Rigot Maxime Lehmann

Vinculin

Enterocyte

10.1046/j.1432-0436.1998.6350305.x

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Citations (12)

BODIPY with Tuned Amphiphilicity as a Fluorogenic Plasma Membrane Probe

Bioconjugate Chemistry (2018)

Mayeul Collot Emmanuel Boutant Maxime Lehmann Andrey S. Klymchenko

Staining of the plasma membrane (PM) is essential in bioimaging, as it delimits the cell surface and provides various information regarding the cell morphology and status. Herein, the lipophilicity of a green emitting BODIPY fluorophore was tuned by gradual functionalization with anchors composed of zwitterionic and aliphatic groups, thus yielding three different amphiphilic dyes. We found that BODIPY bearing one or three anchors failed in efficiently staining the PM: the derivative with one anchor showed low affinity to PM and exhibited strong fluorescence in water due to high solubility, whereas BODIPY with three anchors aggregated strongly in media and precipitated before binding to the PM. In sharp contrast, the BODIPY bearing two anchors (B-2AZ, MemBright-488) formed virtually nonfluorescent soluble aggregates in aqueous medium that quickly deaggregated in the presence of PM, leading to a bright soluble molecular form (quantum yield of 0.92). This fluorogenic response allowed for efficient probing of the PM at low concentration (20 nM) with high signal to background ratio images in mono- as well as two-photon excitation microscopy. B-2AZ proved to selectively stain the PM in a more homogeneous manner than the commercially available fluorescently labeled lectin WGA. Finally, it was successfully used in 3D-imaging to reveal fine intercellular tunneling nanotubes in KB cells and to stain the PM in glioblastoma cells in spheroids.

BODIPY

Lipophilicity

10.1021/acs.bioconjchem.8b00828

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Citations (62)

Nox1-dependent superoxide production controls colon adenocarcinoma cell migration

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (2007)

Amine Sadok Véronique Bourgarel‐Rey Florence Gattacceca Claude Penel Maxime Lehmann

NOX1

Rottlerin

10.1016/j.bbamcr.2007.10.010

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Citations (98)

Structure Function Relationships of KTS Disintegrins and Design of Antiangiogenic Drugs

Letters in Drug Design & Discovery (2009)

Olfa Kallech-Ziri José Luis Ziad Faljoun Jean‐Marc Sabatier Maxime Lehmann

Disintegrins are natural toxins found in snake venom having anti angiogenic activity. The KTS disintegrins group appears to be the most interesting as specific blocking agent of tumor growth. We report the chemical synthesis of three KTS disintegrins (Lebestatin, Obtustatin and Viperistatin) carried out with different substitution. The activity of these synthetic peptides (41 aa) and native Lebestatin purified from venom was compared with cell adhesion and migration assays. Synthetic and native Lebestatin inhibit cell adhesion of PC12 cells at 0.2 nM and integrin-dependent migration of CHO cells at 1 nM. This study shows that Lebestatin has the highest activity followed by Obtustatin and then Viperistatin in the two assays. Circular dichroism spectra of these KTS disintegrins show that their folding is similar. Molecular modeling shows that two arginines (8 and 24) and two lysines (21 and 32) have probably their chemical function interacting with integrins in protruding from the surface of Lebestatin. This study should help to design a lead compound to discover a new family of anti-angiogenic drugs.

10.2174/157018010789869325

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Citations (4)

Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells

Cells (2021)

Elisabete Cruz Da Silva Laurence Choulier Jessica Thevenard-Devy Christophe Schneider Philippe Carl

EGFR (epidermal growth factor receptor), a member of the ErbB tyrosine kinase receptor family, is a clinical therapeutic target in numerous solid tumours. EGFR overexpression in glioblastoma (GBM) drives cell invasion and tumour progression. However, clinical trials were disappointing, and a molecular basis to explain these poor results is still missing. EGFR endocytosis and membrane trafficking, which tightly regulate EGFR oncosignaling, are often dysregulated in glioma. In a previous work, we showed that EGFR tyrosine kinase inhibitors, such as gefitinib, lead to enhanced EGFR endocytosis into fused early endosomes. Here, using pharmacological inhibitors, siRNA-mediated silencing, or expression of mutant proteins, we showed that dynamin 2 (DNM2), the small GTPase Rab5 and the endocytosis receptor LDL receptor-related protein 1 (LRP-1), contribute significantly to gefitinib-mediated EGFR endocytosis in glioma cells. Importantly, we showed that inhibition of DNM2 or LRP-1 also decreased glioma cell responsiveness to gefitinib during cell evasion from tumour spheroids. By highlighting the contribution of endocytosis proteins in the activity of gefitinib on glioma cells, this study suggests that endocytosis and membrane trafficking might be an attractive therapeutic target to improve GBM treatment.

ERBB3

10.3390/cells10113258

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Citations (6)

Antiangiogenic Concentrations of Paclitaxel Induce an Increase in Microtubule Dynamics in Endothelial Cells but Not in Cancer Cells

Cancer Research (2005)

Eddy Pasquier Stéphane Honore Bertrand Pourroy Mary Ann Jordan Maxime Lehmann

Abstract Microtubule-targeted drugs such as paclitaxel exhibit potent antiangiogenic activity at very low concentrations, but the mechanism underlying such an effect remains unknown. To understand the involvement of microtubules in angiogenesis, we analyzed the dynamic instability behavior of microtubules in living endothelial cells [human microvascular endothelial cells (HMEC-1) and human umbilical vascular endothelial cells (HUVEC)] following 4 hours of paclitaxel treatment. Unexpectedly, antiangiogenic concentrations of paclitaxel (0.1-5 nmol/L) strongly increased microtubule overall dynamicity in both HMEC-1 (86-193%) and HUVEC (54-83%). This increase was associated with increased microtubule growth and shortening rates and extents and decreased mean duration of pauses. The enhancement of microtubule dynamics by paclitaxel seemed to be specific to antiangiogenic concentrations and to endothelial cells. Indeed, cytotoxic concentration (100 nmol/L) of paclitaxel suppressed microtubule dynamics by 40% and 54% in HMEC-1 and HUVECs, respectively, as observed for all tested concentrations in A549 tumor cells. After 4 hours of drug incubation, antiangiogenic concentrations of paclitaxel that inhibited endothelial cell proliferation without apoptosis (1-5 nmol/L) induced a slight decrease in anaphase/metaphase ratio, which was more pronounced and associated with increased mitotic index after 24 hours of incubation. Interestingly, the in vitro antiangiogenic effect also occurred at 0.1 nmol/L paclitaxel, a concentration that did not alter mitotic progression and endothelial cell proliferation but was sufficient to increase interphase microtubule dynamics. Altogether, our results show that paclitaxel mediates antiangiogenesis by an increase in microtubule dynamics in living endothelial cells and suggest that the impairment of interphase microtubule functions is responsible for the inhibition of angiogenesis.

Microtubule polymerization

10.1158/0008-5472.can-04-2624

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Citations (133)

Integrin ligation and PKC activation are required for migration of colon carcinoma cells

Journal of Cell Science (1998)

Véronique Rigot Maxime Lehmann Frédéric Andre Noucha Daémi Jacques Marvaldi

ABSTRACT The activation of protein kinases C (PKCs) is an essential step in integrin-dependent cell adhesion and spreading. In this report we examined the effect of the phorbol ester PMA, a PKC activator, on adhesion, spreading and migration of a colon carcinoma cell line, HT29-D4. Treatment with PMA increased the rate of cell spreading and induced the migration of these cells towards purified matrix proteins in haptotaxis assays on Boyden chambers. PMA-induced effects were the result of PKCs activation, as shown by using the inactive isomer 4α-PMA and PKCs inhibitors. The involvement of integrins in the phorbol ester-induced cell migration was demonstrated both by the absence of migration of cells plated on membranes coated with poly-L-lysine and by the use of function blocking antibodies. Thus, interactions between α2β1, α3β1, α6β4, αvβ5, αvβ6 integrins and their specific ligands are necessary for the PKC-mediated migration. However, adhesion, immunoprecipitation and immunocytofluorometry experiments clearly showed that HT29-D4 cell haptotaxis induced by PKC activation is not a consequence of quantitative or qualitative changes in the cell surface integrins. We also demonstrated that PKCs were able to activate the MAP kinase pathway and that the impediment of MAP kinase activation resulted in the loss of cell migration. Moreover, stimulation of the insulin-like growth factor I signalling pathway led to MAP kinase activation and to the induction of cell migration. In addition, the growth factor-induced motility of HT29-D4 cells was affected both by PKC and MAP kinase cascade inhibitors. It thus appears that both integrin ligation and MAP kinase activation by PKCs are required to promote the migration of HT29-D4 cells.

10.1242/jcs.20.111.3119

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Citations (14)

Inhibiting FAK–Paxillin Interaction Reduces Migration and Invadopodia-Mediated Matrix Degradation in Metastatic Melanoma Cells

Cancers (2021)

Antoine Mousson Marlène Legrand Tania Steffan Romain Vauchelles Philippe Carl

The nonreceptor tyrosine kinase FAK is a promising target for solid tumor treatment because it promotes invasion, tumor progression, and drug resistance when overexpressed. Investigating the role of FAK in human melanoma cells, we found that both in situ and metastatic melanoma cells strongly express FAK, where it controls tumor cells’ invasiveness by regulating focal adhesion-mediated cell motility. Inhibiting FAK in human metastatic melanoma cells with either siRNA or a small inhibitor targeting the kinase domain impaired migration but led to increased invadopodia formation and extracellular matrix degradation. Using FAK mutated at Y397, we found that this unexpected increase in invadopodia activity is due to the lack of phosphorylation at this residue. To preserve FAK–Src interaction while inhibiting pro-migratory functions of FAK, we found that altering FAK–paxillin interaction, with either FAK mutation in the focal adhesion targeting (FAT) domain or a competitive inhibitor peptide mimicking paxillin LD domains drastically reduces cell migration and matrix degradation by preserving FAK activity in the cytoplasm. In conclusion, our data show that targeting FAK–paxillin interactions could be a potential therapeutic strategy to prevent metastasis formation, and molecules targeting this interface could be alternative to inhibitors of FAK kinase activity which display unexpected effects.

Paxillin

Invadopodia

PTK2

Podosome

10.3390/cancers13081871

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Citations (28)

Expression and Localization of αv Integrins and Their Ligand Vitronectin in Normal Ovarian Epithelium and in Ovarian Carcinoma

Gynecologic Oncology (1996)

Franck Carreiras Yves Denoux Cathy Staedel Maxime Lehmann François Sichel

Alpha-v beta-3

BETA (programming language)

10.1006/gyno.1996.0225

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Citations (96)