Group name: Proteases and Extracellular Matrix

    Group leader
  • Juan Carlos Rodríguez Manzaneque
  • PHD Students
  • Carlos Peris Torres
  • Orlando Serrano Garrido
  • Silvia Redondo García
  • Technicians
  • Maria del Carmen Plaza Calonge

Presentation Video


The understanding of tumor angiogenesis, basic component for the growth of solid tumors and for the development of metastasis, has suffered great advances during the last years. During the complex formation of tumor neo-vasculture there are many relevant factors, including the major role that extracellular proteases exert at the tumor microenvironment.

The unique contribution of the genomic era revealed the enormous complexity of the extracellular framework, far from the simplistic view of a scaffold and maintenance service. Together with the functional characterization of every existing extracellular protease, it is required to envision such proteolytic activity in a specific scenario. The identification of the specific substrates (“Degradomics”) is a major goal of the scientific community, although it is needed the translation of these findings to proper biological models.

The dynamism of the extracelular milieu is closely related to the functional properties of neo-vascularization events, important for its development, for the appearance of metastasis, and also for the success or fail of therapies. Also, it has been described a major role of the extracellular matrix for the determination of a specific cellular phenotype from a stem cell. Again, it is obvious the inspiring parallelism among the biology of development and the biology of tumors, highlighted by the new challenge that the characterization of cancer stem cells brings up. These cellular entities appear as a paradigm of cellular plasticity, and recent findings show the mimetic capacity of tumor cells to acquire specialized phenotypic properties, including the participation in processes of neo-vascularization.

The detailed characterization of the tumor microenvironment and its remodelling by proteolysis, together with the extracellular and cellular components of the vascular niche, are a current priority, with special relevance for the understanding of mechanisms of drug resistance that certain tumors develop. The convergence of advanced platforms of genomic analysis, together with the functional study of extracellular components in the aberrant scenario of a tumor, appeared as a reliable scenario to investigate for the best knowledge of tumor progression.


  • Characterization of the mechanism of action of ADAMTSs metaloproteases by the identification and functional study of its biological substrates. Proteolysis in the tumor microenvironment occurs by the action of members of several families of proteases, including matrix metaloproteinases (MMPs), transmembrane ADAMs (a disintegrin and metalloprotease) and secreted ADAMTSs (a disintegrin and metalloprotease with thrombospondin motifs). The involvement of ADAMTS proteases during tumor progression has already been highlighted although its actions include apparently paradoxical actions such as the inhibition of angiogenesis, protection against tumor growth, and the induction of metastasis. These studies reveal the high complexity of the mechanism of action of extracellular proteases, and show the necessity to identify the specific substrates that are target of its activity in every tumor microenvironment. The first member of the family, ADAMTS1, represents a clear example of the mentioned complexity. While its anti-angiogenic properties have been confirmed, it has also been reported to have a relevant role for the aggressiveness and metastatic capacity of certain tumors. This research team keeps contributing in the description of some of these properties and, in parallel, they are involved in the identification of ADAMTS1 substrates.
  • Determination of tumor and stem cell plasticity by the modification of the extracellular microenvironment.During the last years the identification of cancer stem cells (CSCs) has been relevant for the understanding of trans-differentiation processes of tumor cells and to interpret their invasive and/or proliferative capacity. As a paradigm of tumor plasticity it has been described the phenomenon of vasculogenic mimicry (VM), defined by the ability of tumor cells to form pseudo-vascular networks, enriched in extracellular matrix, and directly related with the acquisition of a gene signature similar to endothelial cells. This phenomenon was first characterized in highly malignant melanoma tumors, and more recently it also been found in cases of breast, ovarian, lung, and sarcoma tumors. The role of extracellular proteases in this kind of phenomena has been already suggested although the reported data is limited.In this context, there are major findings that reveal the role of physicochemical properties of the matrix for the specialization of stem cells. Mainly it has been characterized the relevance of changes in parameters such as the elasticity of extracellular matrix, and currently it is being studied the way that proteolisis of matrix components modulates these properties. It is required the comparison of differentiation processes to form endothelium from non-transformed stem cells and from plastic tumor cells that carry aberrant signaling pathways. In addition it is needed a detailed analysis of the most intrinsic characteristics of the vascular niche.
  • Studies of functional genomics for the mechanisms of acquisition of endothelial phenotypes by tumor cells. In addition to the close relationship among extracellular proteases and its specific substrates, the characterization of tumor plasticity events in tumor cell lines and in human tumor specimens requires a detailed knowledge of the related gene expression profiles. The evaluation of these gene signatures, together with clinical parameters such as prognosis, drug resistance and metastasis appearance, will allow the identification of new molecules of interest to be evaluated from a functional perspective.


  • Instituto de Salud Carlos III.
  • Consejería de Salud de la Junta de Andalucía.
  • Consejería de Economía, Innovación y Ciencia de la Junta de Andalucía.


Martino-Echarri E, Fernández-Rodríguez R, Rodríguez-Baena FJ, Barrientos-Durán A, Torres-Collado AX, Plaza-Calonge Mdel C, Amador-Cubero S, Cortés J, Reynolds LE, Hodivala-Dilke KM, Rodríguez-Manzaneque JC. Contribution of ADAMTS1 as a tumor suppressor gene in human breast carcinoma. Linking its tumor inhibitory properties to its proteolytic activity on nidogen-1 and nidogen-2. Int J Cancer. 2013 Nov 15;133(10):2315-24.

Travasso RD, Poiré EC, Castro M, Rodríguez-Manzaneque JC, Hernández-Machado A. Tumor angiogenesis and vascular patterning: a mathematical model. PLoS One. 2011;6(5):e19989.

Reynolds LE, Watson AR, Baker M, Jones TA, D'Amico G, Robinson SD, Joffre C, Garrido-Urbani S, Rodriguez-Manzaneque JC, Martino-Echarri E, Aurrand-Lions M, Sheer D, Dagna-Bricarelli F, Nizetic D, McCabe CJ, Turnell AS, Kermorgant S, Imhof BA, Adams R, Fisher EM, Tybulewicz VL, Hart IR, Hodivala-Dilke KM. Tumour angiogenesis is reduced in the Tc1 mouse model of Down's syndrome. Nature. 2010 Jun 10;465(7299):813-7

Casal C, Torres-Collado AX, Plaza-Calonge Mdel C, Martino-Echarri E, Ramón Y Cajal S, Rojo F, Griffioen AW, Rodríguez-Manzaneque JC. ADAMTS1 contributes to the acquisition of an endothelial-like phenotype in plastic tumor cells. Cancer Res. 2010 Jun 1;70(11):4676-86.

Esselens C, Malapeira J, Colomé N, Casal C, Rodríguez-Manzaneque JC, Canals F, Arribas J. The cleavage of semaphorin 3C induced by ADAMTS1 promotes cell migration. J Biol Chem. 2010 Jan 22;285(4):2463-73.

Rodríguez-Manzaneque JC, Carpizo D, Plaza-Calonge Mdel C, Torres-Collado AX, Thai SN, Simons M, Horowitz A, Iruela-Arispe ML. Cleavage of syndecan-4 by ADAMTS1 provokes defects in adhesion. Int J Biochem Cell Biol. 2009 Apr;41(4):800-10.

Torres-Collado AX, Kisiel W, Iruela-Arispe ML, Rodríguez-Manzaneque JC. ADAMTS1 interacts with, cleaves, and modifies the extracellular location of the matrix inhibitor tissue factor pathway inhibitor-2. J Biol Chem. 2006 Jun 30;281(26):17827-37.

Canals F, Colomé N, Ferrer C, Plaza-Calonge Mdel C, Rodríguez-Manzaneque JC. Identification of substrates of the extracellular protease ADAMTS1 by DIGE proteomic analysis. Proteomics. 2006 Apr;6 Suppl 1:S28-35.

Lee NV, Rodriguez-Manzaneque JC, Thai SN, Twal WO, Luque A, Lyons KM, Argraves WS, Iruela-Arispe ML. Fibulin-1 acts as a cofactor for the matrix metalloprotease ADAMTS-1. J Biol Chem. 2005 Oct 14;280(41):34796-804.

Rodríguez-Manzaneque JC, Westling J, Thai SN, Luque A, Knauper V, Murphy G, Sandy JD, Iruela-Arispe ML. ADAMTS1 cleaves aggrecan at multiple sites and is differentially inhibited by metalloproteinase inhibitors. Biochem Biophys Res Commun. 2002 Apr 26;293(1):501-8.