Invadosomes in real life

This issue of Cell Adhesion and Migration has a special focus that contains commentaries, reviews, and original articles exploring different aspects of invadosomes. Remodeling and invasion of the extracellular matrix by cells of various origins are crucial processes not only in physiological but also in pathological conditions. Physiological cell invasion is necessary during fetus implantation and embryogenesis, and matrix remodeling is important for bone homeostasis. Moreover, cell invasion associated with the crossing of the anatomic barriers, such as endothelial basement membrane, is a basic function of the immune cells to respond to and prevent infection. On the other hand, tumor cell invasion is instrumental in the formation of metastasis, the major cause of cancer-related death. Consequently, a better comprehension of the molecular mechanisms underlying this biological process should help define new strategies to prevent metastasis.

For more than 30 y, scientists have been able to identify and study cytoskeletal structures, which are able to adhere to and simultaneously degrade extracellular matrix (ECM) components. These structures, now known as podosomes in normal cells or invadopodia in cancer cells, can be collectively called invadosomes. Invadosomes can be observed not only in mammalians cells but also in zebrafish, in Drosophila or in C. elegans. Invadosomes are F-actin-based structures that are able to degrade the ECM. Their canonical organization comprises an actin core associated with molecules such as cortactin, Tks5, and N-WASP, surrounded by a ring of regulating proteins such as integrin and paxillin, and associated with matrix metalloproteinase (MMPs).^1-5

Invadosomes were identified for the first time in fibroblasts transformed by the oncogene v-Src. This pioneering work has led to a new field of research. Since this discovery, researchers tried to decipher the molecular composition and signaling pathways that control their formation, regulation, and matrix degradation activity.

All manuscripts in this special issue can be summarized around two main questions. The first one concerns the molecular composition of the invadosome that raises the question of its definition. The second one is about the presence of these structures in vivo to define invadosomes as therapeutic targets in the patho-physiological context.

Addressing the first question, one review focuses on the functional architecture of invadopodia in cancer cells. The authors define the molecular composition of three functional domains of invadopodia, including the MMP-based domain involved in matrix degradation, the cytoskeleton-based domain allowing mechanical penetration of the matrix and the integrin adhesome-based domain (corresponding to the adhesive domain) mediating the interaction with the ECM elements.⁶ Of course, a clear crosstalk occurs between these different domains. This point was highlighted in another review, which specifically queries the coupling mechanism between acto-adhesive machinery and the ECM degradation in invadosomes. The authors, in this review, dissect the paradigmatic aspect of invadosomes due to their capacity to interact with the ECM and simultaneously degrade it. The close relationship or the independence between these two functions could be a way to differentiate and classify invadosomes.⁷ The crosstalk between the adhesive ring and the protrusive core is also the central point of the commentary by Koen van den Dries, et al.⁸ This dialog coupled with the molecular composition between the core and the ring are also covered in the commentary by Bravo-Cordeo, et al.⁹ In this commentary, the authors highlight that while the presence of p190RhoGEF at the ring activates RhoC, p190RhoGAP inhibits RhoC at the core to regulate invadopodia protrusion.

Of course a lot of work is still necessary to decipher molecular composition and mechanisms involved in invadosomes’ activity, such as the role of p53 in cell invasion through podosomes and invadopodia.¹⁰ The number of cell types described to be able to form invadosomes is constantly increasing. Depending on the cell-specific functions and the extracellular context studied, invadosomes’ molecular composition and the associated signaling pathways can differ. Based on the literature and new experiments, a study in this special issue aims at establishing a minimal molecular definition of active invadosomes. The authors define a minimal and universal molecular signature of invadosome that includes Cdc42 activity and the presence of Tks5 in order to drive the actin machinery and the proteolytic activity of these invasive structures, respectively (Di Martino, et al., Cell Adh Migr. In press).

The second question about the relevance and the presence of invadosomes in vivo features in most of the manuscripts of the issue, emphasizing the importance of this point. So far, the majority of the invadosomes studies were realized in vitro in 2D and in most of the cases in a gelatin matrix, a non-physiological substrate. All researchers in the field have understood the importance to work and study invadosomes in more physiological conditions. A review by Gould M, et al. describes several elements from the tumor microenvironment, including growth factors, hypoxia, pH, metabolism, and stroma-cell interaction that control the formation and the function of invadosomes.¹¹ During the metastatic process, cells have to degrade ECM elements to cross the anatomic barriers such as the epithelial and endothelial basement membranes. These basement membranes play structuring, protecting, and polarizing roles and their composition varies between tissues. In the review by the Vignejvic group, the authors analyze the composition of different basement membranes and examine the different strategies cells use to breach these membranes.¹² In most cases, the cellular environment is in three dimensions, and one of the reviews discusses the advantages and limitations of 2D and 3D contexts to analyze the presence and the function of the invadosomes, in particular for macrophages.¹³

Several examples already establish the presence of invadosomes in vivo. The first example was the sealing zone observed in osteoclasts that is necessary for bone degradation. One of the reviews focuses on the recent advancements on podosome structure and the regulatory pathways in osteoclasts. The authors discuss the distinct functions of different podosome patterns during the lifespan of a single osteoclast.¹⁴ Now, the challenge is to study invadosomes in vivo. One review regroups all the studies, which analyze invadosomes and basement membrane invasion in vivo.¹⁵ The authors cite articles demonstrating cancer forming invadopodia in vivo and studies showing invadopodia breaching the basement membrane during C. elegans organogenesis. A complementary commentary emphasizes the importance (and the difficulties) of visualizing and analyzing invadosomes in vivo.¹⁶ The authors suggest that a combination of different approaches will be necessary to fully understand invadosomes and to define a cellular-decision model for tumor cell motility.

To achieve the proposed objectives made by the authors who participated in this special issue, including the visualization and analysis of the invadosomes in vivo and more globally cell invasion, new technical developments are needed. Already, high-level technologies are allowing us to move forward in these issues, such as intravital microscopy, high-resolution microscopy, biosensor, optogenetic approaches, and many others.

Finally, I would like to thank the leading experts in this field who kindly contributed to or peer-reviewed this special issue. I would also like to use this opportunity to pay a tribute to the career of one of my mentors, Pierre Jurdic, who is newly retired. A part of Pierre’s career allowed major advances in understanding the mechanisms that regulate podosomes and the sealing zone in osteoclasts. Pierre has been actively involved in the emergence of this field and has always been an active and valued member of this community. On behalf of the invadosome community, I wish him a very good and a well-deserved retirement.

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Figure 1. Dr Frédéric Saltel received his PhD Bone Biology from the University Paris VII (Paris, France) in 2004. Under the supervision of Dr Pierre Jurdic (Ens-Lyon, France), he studied the actin dynamic of podosomes and sealing zone in osteoclasts, along differentiation and degradation processes. After that, and to better understand interaction between extracellular matrix and cell, he joined the Dr Wehrle-Haller group at CMU (Geneva, Switzerland). During his post-doc he studied integrin beta 3 activation and established the animo acid sequence necessary for interaction between talin and the beta 3 subunit to form integrin cluster. After his return in France in 2007, to work on invadosomes, he joined the in E. Genot’s group in Bordeaux where he developed an expertise in endothelial cells. He obtained a permanent position at the INSERM in 2008. In 2010, he joined Jean Rosenbaum’s laboratory at U1053 (Bordeaux) and highlighted the existence of an new class of invadosomes induced by type I collagen fibrils. And now, he continues in this way to decipher molecular mechanisms involved in formation and activation of invadosomes in vitro and in vivo.