RESEARCH GROUP
ADVANCED THERAPIES AREA
EPITHELIAL CARCINOGENESIS RESEARCH GROUP
INVESTIGATORS:
Esther Grueso Hierro Ph.D.
Susana Álvarez Losada Ph.D.
EXTERNAL COLLABORATORS:
Miguel Quintanilla Ávila Ph.D.
Lucía Montero Montero Ph.D.
PRE-DOCTORAL STUDENTS:
Santiago Beltrán Álvarez
Rocío Jarcovsky González (Master Student)
LINE OF INVESTIGATION
Role of Podoplanin and CD44 in epithelial carcinogenesis and cutaneous homeostasis.
SUMMARY OF THE RESEARCH PROJECT
Squamous cell carcinomas (SCCs) are among the most frequent malignant neoplasms and represent a major cause of death worldwide. SCC arise from the stratified epithelia of diverse anatomical locations; being frequently found in skin, head and neck, oesophagus, lung and cervix. Their incidence is abruptly rising due to increased exposure to carcinogens, such as UV radiation related to sun exposure, smoking, alcohol consumption or human papilloma virus (HPV) infection. Among the main causes of death in SCC patients are injuries caused by the surgical removal of tumours, the formation of new secondary tumours and metastatic sites. Additionally, late diagnosis of the disease is also one of the main aggravating factors.
Our research group has pioneered the discovery of the involvement of a small molecule known as “podoplanin” in SCC progression. It is a key small molecule, whose biological function is not fully understood, and whose expression in tumour cells and/or cells within the tumour environment, seems to promote tumour invasion. Our objective is to expand existing basic knowledge on the biology of carcinomas, strengthening the molecular mechanisms through which this new molecule and/or associated molecules could actively participate in their development. To investigate the role of podoplanin in the biogenesis and progression of epidermoid carcinomas, we use animal and cellular models combined with different microscopy, cellular and molecular biology strategies. Increasing our knowledge about the initial events of tumour invasion will help us to establish a better prognosis of the disease in earlier stages and define new therapeutic strategies.
PUBLICATIONS RELATED TO THE LINE OF RESEARCH
Moncho-Amor V, Pintado-Berninches L, Ibañez de Cáceres I, Martín-Villar E,Quintanilla M, Chakravarty P, Cortes-Sempere M, Fernández-Varas B, Rodriguez-Antolín C, de Castro J, Sastre L, Perona R. Role of Dusp6 Phosphatase as a Tumor Suppressor in Non-Small Cell Lung Cancer. Int J Mol Sci. 2019 Apr 25;20(8). pii: E2036. doi:10.3390/ijms20082036. PubMed PMID: 31027181; PubMedCentral PMCID: PMC6514584.
Quintanilla M, Montero-Montero L, Renart J, Martín-Villar E. Podoplanin in Inflammation and Cancer. Int J Mol Sci. 2019 Feb 6;20(3). pii: E707. doi:10.3390/ijms20030707. Review. PubMed PMID: 30736372; PubMed Central PMCID:PMC6386838.
da Silva IL, Montero-Montero L, Martín-Villar E, Martin-Pérez J, Sainz B,Renart J, Toscano Simões R, Soares Veloso É, Salviano Teixeira C, de Oliveira MC,Ferreira E, Quintanilla M. Reduced expression of the murine HLA-G homolog Qa-2 is associated with malignancy, epithelial-mesenchymal transition and stemness in breast cancer cells. Sci Rep. 2017 Jul 24;7(1):6276. doi:10.1038/s41598-017-06528-x. PubMed PMID: 28740236; PubMed Central PMCID:PMC5524840.
Luengo-Gil G, Calvo MI, Martín-Villar E, Águila S, Bohdan N, Antón AI, Espín S, Ayala de la Peña F, Vicente V, Corral J, Quintanilla M, Martínez-Martínez I.Antithrombin controls tumor migration, invasion and angiogenesis by inhibition of enteropeptidase. Sci Rep. 2016 Jun 8;6:27544. doi: 10.1038/srep27544. PubMed PMID: 27270881; PubMed Central PMCID: PMC4897635.
Carrasco-Ramírez P, Greening DW, Andrés G, Gopal SK, Martín-Villar E, Renart J, Simpson RJ, Quintanilla M. Podoplanin is a component of extracellular vesicles that reprograms cell-derived exosomal proteins and modulates lymphatic vessel formation. Oncotarget. 2016 Mar 29;7(13):16070-89. doi: 10.18632/oncotarget.7445. PubMed PMID: 26893367; PubMed Central PMCID: PMC4941298.
Renart J, Carrasco-Ramírez P, Fernández-Muñoz B, Martín-Villar E, Montero L, Yurrita MM, Quintanilla M. New insights into the role of podoplanin in epithelial-mesenchymal transition. Int Rev Cell Mol Biol. 2015;317:185-239. doi:10.1016/bs.ircmb.2015.01.009. Epub 2015 Mar 5. Review. PubMed PMID: 26008786.
Pérez-Gómez E, Andradas C, Blasco-Benito S, Caffarel MM, García-Taboada E, Villa-Morales M, Moreno E, Hamann S, Martín-Villar E, Flores JM, Wenners A, Alkatout I, Klapper W, Röcken C, Bronsert P, Stickeler E, Staebler A, Bauer M, Arnold N, Soriano J, Pérez-Martínez M, Megías D, Moreno-Bueno G, Ortega-Gutiérrez S, Artola M, Vázquez-Villa H, Quintanilla M, Fernández-Piqueras J, Canela EI,McCormick PJ, Guzmán M, Sánchez C. Role of cannabinoid receptor CB2 in HER2 pro oncogenic signaling in breast cancer. J Natl Cancer Inst. 2015 Apr 8;107(6):djv077. doi: 10.1093/jnci/djv077. Print 2015 Jun. PubMed PMID: 25855725.
del Castillo G, Sánchez-Blanco E, Martín-Villar E, Valbuena-Diez AC, Langa C, Pérez-Gómez E, Renart J, Bernabéu C, Quintanilla M. Soluble endoglin antagonizes Met signaling in spindle carcinoma cells. Carcinogenesis. 2015 Feb;36(2):212-22. doi: 10.1093/carcin/bgu240. Epub 2014 Dec 10. PubMed PMID: 25503931.
Martín-Villar E, Borda-d’Agua B, Carrasco-Ramirez P, Renart J, Parsons M, Quintanilla M, Jones GE. Podoplanin mediates ECM degradation by squamous carcinoma cells through control of invadopodia stability. Oncogene. 2015 Aug 20;34(34):4531-44. doi: 10.1038/onc.2014.388. Epub 2014 Dec 8. PubMed PMID:25486435; PubMed Central PMCID: PMC4430312.
Griera M, Martin-Villar E, Banon-Rodríguez I, Blundell MP, Jones GE, Anton IM, Thrasher AJ, Rodriguez-Puyol M, Calle Y. Integrin linked kinase (ILK)regulates podosome maturation and stability in dendritic cells. Int J Biochem Cell Biol. 2014 May;50:47-54. doi: 10.1016/j.biocel.2014.01.021. Epub 2014 Feb 6.PubMed PMID: 24508783; PubMed Central PMCID: PMC3998073.
Yurrita MM, Fernández-Muñoz B, Del Castillo G, Martín-Villar E, Renart J, Quintanilla M. Podoplanin is a substrate of presenilin-1/γ-secretase. Int J Biochem Cell Biol. 2014 Jan;46:68-75. doi: 10.1016/j.biocel.2013.11.016. Epub 2013 Nov 22. PubMed PMID: 24275092.
Pérez-Gómez E, Jerkic M, Prieto M, Del Castillo G, Martín-Villar E, Letarte M, Bernabeu C, Pérez-Barriocanal F, Quintanilla M, López-Novoa JM. Impaired wound repair in adult endoglin heterozygous mice associated with lower NO bioavailability. J Invest Dermatol. 2014 Jan;134(1):247-255. doi:10.1038/jid.2013.263. Epub 2013 Jun 13. PubMed PMID: 23765132.
Fernández-Muñoz B, Yurrita MM, Martín-Villar E, Carrasco-Ramírez P, Megías D, Renart J, Quintanilla M. The transmembrane domain of podoplanin is required for its association with lipid rafts and the induction of epithelial-mesenchymal transition. Int J Biochem Cell Biol. 2011 Jun;43(6):886-96. doi:10.1016/j.biocel.2011.02.010. Epub 2011 Mar 3. PubMed PMID: 21376833.
Martín-Villar E, Fernández-Muñoz B, Parsons M, Yurrita MM, Megías D,Pérez-Gómez E, Jones GE, Quintanilla M. Podoplanin associates with CD44 to promote directional cell migration. Mol Biol Cell. 2010 Dec;21(24):4387-99. doi:10.1091/mbc.E10-06-0489. Epub 2010 Oct 20. PubMed PMID: 20962267; PubMed Central PMCID: PMC3002391.
Larriba MJ, Martín-Villar E, García JM, Pereira F, Peña C, de Herreros AG, Bonilla F, Muñoz A. Snail2 cooperates with Snail1 in the repression of vitamin D receptor in colon cancer. Carcinogenesis. 2009 Aug;30(8):1459-68. doi:10.1093/carcin/bgp140. Epub 2009 Jun 5. PubMed PMID: 19502595.
Martín-Villar E, Yurrita MM, Fernández-Muñoz B, Quintanilla M, Renart J.Regulation of podoplanin/PA2.26 antigen expression in tumour cells. Involvement of calpain-mediated proteolysis. Int J Biochem Cell Biol. 2009 Jun;41(6):1421-9. doi: 10.1016/j.biocel.2008.12.010. Epub 2008 Dec 25. PubMed PMID: 19146981.
Martín-Villar E, Megías D, Castel S, Yurrita MM, Vilaró S, Quintanilla M. Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition. J Cell Sci. 2006 Nov 1;119(Pt 21):4541-53. Epub 2006 Oct 17. PubMed PMID: 17046996.
Martín-Villar E, Scholl FG, Gamallo C, Yurrita MM, Muñoz-Guerra M, Cruces J, Quintanilla M. Characterization of human PA2.26 antigen (T1alpha-2, podoplanin), a small membrane mucin induced in oral squamous cell carcinomas. Int J Cancer. 2005 Mar 1;113(6):899-910. PubMed PMID: 15515019.
Muñoz-Guerra MF, Marazuela EG, Martín-Villar E, Quintanilla M, Gamallo C. Prognostic significance of intratumoral lymphangiogenesis in squamous cell carcinoma of the oral cavity. Cancer. 2004 Feb 1;100(3):553-60. PubMed PMID: 14745872.
PROJECTS (last 5 years)
Role of podoplanin in the malignant progression of epithelial cancer. Relevance of podoplaning-CD44. Ministry of Economy, Industry and Competitiveness (Ministerio de Economia, Industria y Competitividad – MINECO). SAF2017-84183-R. Duration: January 2018-December 2021.
Role of glycoproteins of the cell surface podoplanin and endoglin in skin homeostasis and cutaneous carcinogenesis. MINECO: SAF2013-46183. January 2014-December 2017.
Skin homeostasis and pathology. Development of cellular and animal model systems for the study of epithelial signalling pathways and novel therapeutic approaches (skin model). Community of Madrid (Comunidad de Madrid). January 2012-December 2015.
Tumour progression through non-canonical signalling transmembrane glycoproteins. Studies on podoplanin/pa2.26 antigen and endoglin. MICINN: SAF2010-19152. January 2011-December 2014.
Molecular mechanisms underlying podoplanin-mediated 3d invasion of SCC cells. CANCER RESEARCH UK (C7125/A13651). March 2012- April 2013.
Institute of Life Sciences
9:00 a.m. to 2:00 p.m. Monday to Friday