Research project

Understanding the metastasis cascade: still a long way ahead

Metastasis can be considered as the end product of a multistep bio-mechano-chemical process where cancer cells disseminate to distant organs and home in a new tissue microenvironment (Fig.1). Metastases are resistant to multiple therapies and are responsible for the large majority of cancer-related deaths. It is now clear that the invasion-angiogenesis-metastasis cascade is not only dependent on genetic and epigenetic alterations within cancer cells, but also involves non-neoplastic stromal cells that contribute to cancer progression. However, the molecular and cellular mechanisms driving metastasis formation remain to be elucidated and better described in a realistic in vivo context. In this context, tumor cells interact with their surrounding microenvironment and corrupt it to their own benefit. For example, exosomes are small extracellular vesicles, which recently emerged as potent mediators involved in this communication. These vesicles are from an endosomal origin, contain proteins, mRNAs, non-coding RNAs and DNA; they circulate in all our body fluids and can be internalized by specific distant cells and ultimately deliver a functional message. Tumor cells release large amounts of exosomes bearing tumoral markers, which can subsequently disseminate at distance. In addition, tumor exosomes contain pro-metastatic factors that shape pre-metastatic niches (PMN), before the actual arrival of tumor cells, while determining tumor metastatic organo-tropism. These properties have promoted exosomes as new targets for anti-tumoral therapies and major candidates for non-invasive diagnosis in cancer using liquid biopsies (blood and urine), and intense research is currently conducted to identify exosome-carried biomarkers.

More informations on Tumor Biomechanics Lab website

MAJOR COLLABORATIONS

Jochen GUCK (MPI, Erlangen) : Cell Mechanics, Hector PEINADO (CNIO, Madrid), Julie GAVARD (Nantes) : EVs, Yannick SCHWAB (EMBL, Heidelberg) : Correlative microscopy, Sylvain GIOUX (ICube, Strasbourg), Frank WINKLER (DKFZ, Heidelberg): Intravital imaging, Pierre MANGIN (EFS, Strasbourg): Hemodynamics, Andrey KLYMCHENKO and Nicolas ANTON (Faculté de Pharmacie, Strasbourg): Intravital imaging and tumor targeting, Philippe CHAVRIER and Matthieu PIEL (Curie, Paris): Correlative microscopy of the metastasis cascade.

FUNDING

  • Ongoing: ARC (Cancer Research Association) (2018-2021) in a collaborative project, INCA (National French Cancer Agency) grant (2015-2019), Plan Cancer (French Cancer Research Plan) grant (2015-2019), INCA (National French Cancer Agency) in a collaborative project (2015-2019), INCA (National French Cancer Agency) in a collaborative project (2016-2019), Ligue contre le Cancer (2019), Canceropole Est Interregional grant (2018-19)
  • Finalized: SATT Conectus (2018) grant, Canceropole Est cross-border grant (2016), Roche fundamental Research grant (2014), Ligue contre le Cancer (2013-14-17-18), University of Strasbourg starting grant (2012-13), Marie Curie IEF Post-doctoral fellow (2010-2010), CNIC Post-doc fellowship (2008-10), ARC (Cancer Research Association) Ph.D fellowship (2007), French Ministry Ph.D fellowship (2003-06)

Main Publications (2016-2019)

Joseph H.R. Hetmanski, Henry de Belly, Ignacio Busnelli, Tom Waring, Roshna V. Nair, Vanesa Sokleva, Oana Dobre, Angus Cameron, Nils Gauthier, Christophe Lamaze, Joe Swift, Aránzazu del Campo, Toby Starborg, Tobias Zech, Jacky G.Goetz, Ewa Paluch, Jean-Marc Schwartz and Patrick T. Caswell. Membrane tension orchestrates rear retraction in matrix directed cell migration. Developmental Cell. In press

Nilda Vanesa Ayala-Nunez, Follain Gautier, François Delalande, Aurélie Hirschler, Emma Partiot, Gillian Hale, Brigid Bollweg, Judith Roels, Maxime Chazal, Florian Bakoa, Margot Carocci, Sandrine BOURDOULOUS, Orestis Faklaris, Sherif Zaki, Anita Eckly, Béatrice Uring-Lambert, Frédéric Doussau, Sarah Cianferani, Christine Carapito, Frank Jacobs, Nolwenn Jouvenet, Jacky G. Goetz, and Raphael Gaudin. Zika virus enhances monocyte adhesion and transmigration favoring viral dissemination to neural cells. Nature Communications. In press.

Naël Osmani, Gautier Follain, Marìa Jesùs Garcia Leòn, Olivier Lefebvre, Ignacio Busnelli, Annabel Larnicol, Sébastien Harlepp, Jacky G. Goetz.Metastatic tumor cells exploit their adhesion repertoire to counteract shear forces during intravascular arrest. Cell Reports, 2019, Sep 3;28(10):2491-2500

Vincent Hyenne*, Shima Ghoroghi, Mayeul Collot, Follain Gautier, Harlepp Sebsatien, Mary Benjamin, Sébastien Harlepp, Jack Bauer, Luc Mercier, Ignacio Busnelli, Olivier Lefebvre, Nina Fekonja, Pedro Machado, Joanna Bons, François Delalande, Ana Isabel Amor, Susana Garcia Silva, Frederik J. Verweij, Guillaume Van Niel, Héctor Peinado, Christine Carapito, Andrey S. Klymchenko and Jacky G. Goetz*. Studying the fate of tumor extracellular vesicles at high spatiotemporal resolution using the zebrafish embryo. Developmental Cell • 2019, Feb 25;48(4):554-572, BioRxiv doi: https://doi.org/10.1101/380238

Frederik J Verweij, Celine Revenu, Guillaume Arras, Florent Dingli, Loew Damarys, Gautier Follain, Guillaume Allio, Jacky G.Goetz, Philippe Herbomel, Filippo Del Bene, Graca Raposo, Guillaume van Niel. Live tracking of inter-organ communication by endogenous exosomes in vivo. Developmental Cell • 2019, Feb 25;48(4):573-589, BioRxiv doi: https://doi.org/10.1101/380311

Ezzoukhry Z, Henriet E, Cordelières FP, Dupuy JW, Maître M, Gay N, Di-Tommaso S, Mercier L, Goetz JG, Peter M, Bard F, Moreau V, Raymond AA, Saltel F. Combining laser capture microdissection and proteomics reveals an active translation machinery controlling invadosome formation. Nat Commun. 2018 May 23;9(1):2031.

Follain G., Osmani N., Azevedo SA., Allio G., Mercier L., Karreman MA., Solecki G., Garcia-Leon MJ., Lefebvre O., Fekonja N., Hille C., Chabannes V., Dollé G., Metivet T., Prudhomme C., Pichot A., Paul N., Carapito R., Barham S., Ruthensteiner B., Kemmling A., Siemonsen S., Schneider T., Fiehler J., Glatzel M., Winkler F., Schwab Y., Pantel K., Harlepp S., Goetz JG. Hemodynamic forces tune the arrest, adhesion and extravasation of circulating tumor cells. Developmental Cell • 2018, Apr 9;45(1):33-52

Sébastien Harlepp, Fabrice Thalmann, Gautier Follain, Jacky G. Goetz. Hemodynamic forces can be accurately measured in vivo with optical tweezers. Molecular Biology of the Cell • 2017 Nov 7;28(23):3252-3260

Redouane Bouchaala#, Luc Mercier#, Bohdan Andreiuk , Yves Mély, Thierry Vandamme, Nicolas Anton*, Jacky G. Goetz* and  Andrey S. Klymchenko* (# equal contribution, *co-corresponding authors). Integrity of lipid nanocarriers in bloodstream and tumor quantified by near-infrared ratiometric FRET imaging in living mice. Journal of Controlled Release • 2016 • Aug 28;236:57-67(Highlighted in the local Radio “France Bleu Alsace” : https://www.francebleu.fr/infos/sante-sciences/des-nano-particules-etanches-pour-mieux-soigner-le-cancer-mises-au-point-strasbourg-1474779329)

Luc Mercier, Johann Böhm, Nina Fekonja, Guillaume Allio, Yves Lutz, Marc Koch, Jacky G. Goetz* and Jocelyn Laporte* (*co-corresponding authors). In vivo imaging of skeletal muscle in mice highlights muscle defects in a mouse model of myotubular myopathy. Intravital • 2016 • 5(1): 1-10. (Selected for cover image)

Matthia A. Karreman, Luc Mercier, Nicole L. Schieber, Gergely Solecki, Guillaume Allio, Frank Winkler, Bernhard Ruthensteiner, Jacky G. Goetz* and Yannick Schwab*. (*Co-corresponding authors). Fast and precise targeting of single tumor cells in vivo by multimodal correlative microscopy Journal of Cell Science • 2016 •129(2): 444-456. (Highlighted by Journal of Cell Science, INSERM, Sciences et Avenir, locals newpapers (DNA) and FR3 Alsace)

Hyenne V, Apaydin A, Rodriguez D, Lefebvre O, Spiegelhalter C, Hoff S, Diem M, Schwab Y, Goetz JG, Labouesse M. RAL-1 controls exosome secretion by affecting MVB biogenesis and fusion with the plasma membrane. Journal of Cell Biology • 2015 • 211:27-37. (Highlighted by Journal of Cell Biology, INSERM and CNRS)

Methods:

Gautier Follain, Naël Osmani, Cédric Fuchs, Guillaume Allio, Sébastien Harlepp, Jacky G.Goetz. Using the zebrafish embryo to dissect the early steps of the metastasis cascade. Methods in Molecular Biology • 2018 2018;1749:195-211

M.A. Karreman, B. Ruthensteiner, L. Mercier, N.L. Schieber, G. Solecki, F. Winkler, J.G. Goetz and Y. Schwab. Find your way with x-ray: Efficient correlation between in vivo imaging and 3DEM using microCT.  Methods in Molecular Biology • 2017 140:277-301

Reviews:

Gautier Follain, David Herrmann, Sébastien Harlepp, Vincent Hyenne, Naël Osmani, Sean Warren, Paul Timpson and Jacky G. Goetz.. Fluids and mechanics in tumor transit: shaping metastasis. Nature Reviews Cancer • In Press.

Osmani N and Goetz JG. Zebrafish puts metastasis in the spotlight. Trends in Cancer • In press.

Verweij FJ, Hyenne V, Van Niel G, Goetz JG. Extracellular Vesicles: Catching the Light in Zebrafish. Trends in Cell Biology • 2019.

Goetz JG. Tumor metastases go with the flow. Science (invited) • 2018, 362(6418):999-1000

Follain G., Goetz JG. Synergistic mechano-chemical sensing by vascular cilia. Trends in Cell Biology • 2018, May 2. pii: S0962-8924(18)30069-2

Hyenne V, Goetz JG. Extracellular vesicles on the wire. Cell Adhesion and Migration • 2017 • 11(2):121-123

Hyenne V, Lefebvre O, Goetz JG. Going live with tumor exosomes and microvesicles in vivo. Cell Adhesion and Migration • 2017 • 11(2):173-186

Karreman M, Hyenne V, Schwab Y* and GoetzJG* (* Co-corresponding authors). Intravital Correlative Microscopy: Imaging Life at the Nanoscale. Trends in Cell Biology • 2016 • 26(11):848-863

Follain G, Mercier L, Osmani L, Harlepp S and  GoetzJG. Seeing is believing: multi-scale spatio-temporal imaging towards in vivo cell biology. Journal of Cell Science • 2016 •130(1):23-38

Di Martino J, Henriet e., Ezzoukhry Z, GoetzJ.G, Moreau V. and Saltel F. The microenvironment controls invadosome plasticity. Journal of Cell Science • 2016 • 129(9):1759-68