Endocytosis, cytoskeleton and cell migration

Endocytosis, cytoskeleton and cell migration

This team belongs to the UMR 1279 - Tumor cell dynamics

The overall objective of our lab is to understand how the mechanical properties of the tumoral environment influence cancer cell migration.

Research topics

Our projects aim to understand the functions of clathrin-coated structures (CCSs) associated with changing physical parameters of the tumour environment. CCSs recruit surface receptors and package them in vesicles that bud into the cytosol. This endocytosis allows the absorption of nutrients but also the control of signalling pathways triggered by the receptors. As a result, the deregulation of endocytosis has been linked to many pathological situations, including cancers.

The development of tumours is accompanied by changes in the mechanical characteristics of tissues. In addition, when cancer cells escape the primary tumor, they migrate into an environment with unique 3D topological characteristics. However, it is not known how the physical parameters of the microenvironment affect CCSs and what the consequences are for cancer cells. Our published and preliminary work indicates that substrate stiffness (which is increased in tumour tissues) and environmental topology (when composed of fibres) may prevent CCSs from budding and achieving endocytosis. This frustration modulates the functions of CCSs, which then act as signalling platforms or adhesive structures and even as cues deposited behind migrating cells that define a road for the migration of following cells.

We are studying how frustrated CCSs help cancer-associated fibroblasts to migrate towards rigid substrates and how they create pathways for cancer cell migration. We are also studying how the topology of the microenvironment modulates the dynamics and functions of CCSs in cancer cells by regulating the adjustment of membrane tension and how this affects cancer cell migration in complex environments.

Major publications

• Lock JG, Baschieri F, Jones MC, Humphries JD, Montagnac G, Strömblad S, Humphries MJ. Clathrin-containing adhesion complexes. J Cell Biol. 2019 Jul 1;218(7):2086-2095. doi: 10.1083/jcb.201811160. Epub 2019 Jun 17.
• Baschieri F, Dayot S, Elkhatib N, Ly N, Capmany A, Schauer K, Betz T, Vignjevic DM, Poincloux R, Montagnac G. Frustrated endocytosis controls contractility-independent mechanotransduction at clathrin-coated structures. Nat Commun. 2018 Sep 20;9(1):3825. doi: 10.1038/s41467-018-06367-y.
• Elkhatib N, Montagnac G. Frustrated endocytosis supports 3D cell migration. Med Sci (Paris). 2018 Jun-Jul;34(6-7):522-524. doi: 10.1051/medsci/20183406009. Epub 2018 Jul 31.
• Janke C, Montagnac G. Causes and Consequences of Microtubule Acetylation. Curr Biol. 2017 Dec 4;27(23):R1287-R1292. doi: 10.1016/j.cub.2017.10.044.
• Elkhatib N, Bresteau E, Baschieri F, Rioja AL, van Niel G, Vassilopoulos S, Montagnac G. Tubular clathrin/AP-2 lattices pinch collagen fibers to support 3D cell migration. Science. 2017 Jun 16;356(6343). pii: eaal4713. doi: 10.1126/science.aal4713.
• De Franceschi N, Arjonen A, Elkhatib N, Denessiouk K, Wrobel AG, Wilson TA, Pouwels J, Montagnac G, Owen DJ, Ivaska J. Selective integrin endocytosis is driven by interactions between the integrin α-chain and AP2. Nat Struct Mol Biol. 2017 Feb 6;24(2):194. doi: 10.1038/nsmb0217-194b.
• Ly N, Elkhatib N, Bresteau E, Piétrement O, Khaled M, Magiera MM, Janke C, Le Cam E, Rutenberg AD, Montagnac G. αTAT1 controls longitudinal spreading of acetylation marks from open microtubules extremities. Sci Rep. 2016 Oct 18;6:35624. doi: 10.1038/srep35624.
• Marchesin V, Castro-Castro A, Lodillinsky C, Castagnino A, Cyrta J, Bonsang-Kitzis H, Fuhrmann L, Irondelle M, Infante E, Montagnac G, Reyal F, Vincent-Salomon A, Chavrier P. ARF6-JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion.J Cell Biol. 2015 Oct 26;211(2):339-58. doi: 10.1083/jcb.201506002.
• Boissan M, Montagnac G, Shen Q, Griparic L, Guitton J, Romao M, Sauvonnet N, Lagache T, Lascu I, Raposo G, Desbourdes C, Schlattner U, Lacombe ML, Polo S, van der Bliek AM, Roux A, Chavrier P. Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling. Science. 2014 Jun 27;344(6191):1510-5. doi: 10.1126/science.1253768.
• Montagnac G, Meas-Yedid V, Irondelle M, Castro-Castro A, Franco M, Shida T, Nachury MV, Benmerah A, Olivo-Marin JC, Chavrier P. αTAT1 catalyses microtubule acetylation at clathrin-coated pits. Nature. 2013 Oct 24;502(7472):567-70. doi: 10.1038/nature12571. Epub 2013 Oct 6

• Guillaume Montagnac, PI Inserm
• Nadia Elkhatib, Inserm staff scientist (CRCN)
• Francesco Baschieri, post-doc
• Kseniia Porshneva, post-doc
• Enzo Bresteau, post-doc
• Nathalie Ly, Engineer
• Julie Bruna-Gauchoux, PhD student
• Samuel Tettarasar, PhD student