Molecular Oncology

Summary

The main interest of our lab is the characterization of the molecular bases of cancer, with special emphasis on tumor aggressiveness. In the vast majority of cancers lethality is associated to the development of metastasis. Therefore, understanding the mechanisms that allow tumors cells to leave the primary tumor and colonize the organism is critical. A prominent role in this process is played by signalling pathways which become entangled in oncogenic circuits that reprogrammes tumor cell behaviour. We are interested in understanding how these circuits may promote the acquisition of aggressive tumor phenotypes.

Research Lines

Molecular basis of tumor aggressiveness

The prolil isomerase Pin1 acts as a global modulator of cell signalling able to change the response to a combination of stimuli by selectively acting on phosphorylated protein substrates. Abnormally high Pin1 levels may contribute with tumor progression by different mechanisms that perturb cell signalling. To deal with the daunting complexity of oncogenic signalling we are using zebrafish embryos as biosensors able to unveil the action of signals arising from oncogenic lesions in vivo. Studying alterations in embryogenesis we are trying to understand which signalling pathways and which cell types may be affected by Pin1 misfunction. A particularly deleterious connection in oncogenic signaling circuitry is the cooperation between Pin1 and p53 point mutants. Missense mutations on the p53 gene are frequently found in human tumors and as a consequence p53 point mutants acquire new functions that subvert an efficient tumor suppressor pathway into a mechanism of tumor aggressiveness that promotes the development of metastasis. Through binding and amplification of mutant p53 oncogenic function, Pin1 and mutant p53 establish a molecular axis that links oncogenic signalling with downstream mechanisms of aggressiveness. We are working on the characterization of the molecular mechanisms underlying this cooperation focusing on the ability of mutant p53 to alter gene expression. We are also generating transgenic fish which will provide a novel in vivo model to study the consequences of chronic Pin1 overexpression and will allow us to develop other cancer models by combining Pin1 misfunction with other oncogenic alterations such as Ras hyperactivation or p53 mutation. The ability of Pin1 to act simultaneously on several different substrates makes it an ideal candidate for therapy design, since manipulation of Pin1 activity may contribute to amplify the response elicited by pharmacologic agents. In our lab we are studying the potential of Pin1 inhibition to be applied in combined therapies for cancer treatment.

Selected Publications

  • Girardini, J.E., Napoli, M., Piazza, S., Rustighi, A., Marotta, C., Radaelli, E., Capaci, V., Jordan, L., Quinlan, P., Thompson, A., Mano, M., Rosato, A., Crook, T., Scanziani, E., Means A.R., Lozano, G., Schneider, C., and Del Sal, G. (2011). A Pin1/Mutant p53 Axis Promotes Aggressiveness in Breast Cancer. Cancer Cell. 20, 79-91.
  • Girardini, J.E., Del Sal, G. Improving pharmacological rescue of p53 function: RITA targets mutant p53 (2010) News & Views. Cell Cycle. 9 (11), 2059-2062.
  • Guida E., Bisso A., Fenollar-Ferrer C., Napoli M., Anselmi C., Girardini J.E., Carloni P. and Del Sal G. “Peptide Aptamers targeting mutant p53 induce apoptosis in tumor cells. (2008). Cancer Research. 68, 6550-6558.
  • Mantovani, F., Tocco, F., Girardini, J., Smith, P., Gasco, M., Lu, X., Crook, T. and Del Sal, G (2007)The prolyl-isomerase Pin1 orchestrates p53 acetylation and dissociation from the apoptosis inhibitor iASPP. Nature Structural and Molecular Biology. 14, 912-920.

Collaborators

  • Dr. Gianni Del Sal. Molecular Oncology Unit. Laboratorio Nazionale CIB (LNCIB). Trieste, Italia.
  • Dra. Marina Mione. Karlsruhe Institute of Technology, Alemania

Grants

  • Instituto Nacional del Cáncer (INC)
  • Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT)
  • Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)

Director

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Girardini, Javier E.
Core CCT
Email: girardini@ibr-conicet.gov.ar
Phone: +54 341 4237070
Office Extension: 651
Laboratory Extension: 615

Researchers

  • Marianela Masin

Doctoral fellows

  • Carla M. Borini Etichetti
  • Solange Ibarra Valdez
  • Carolina Di Benedetto

Undergraduate Students

  • Maria Nicol Arroyo

Imágenes

Líneas transgénicas de pez cebra. Los peces que expresan proto-oncogenes fusionados a GFP representan una valiosa herramienta para el estudio de mecanismos oncogénicos.

Representación esquemática del mecanismo propuesto para la cooperación de Pin1 y p53 mutante en el desarrollo de fenotipos tumorales agresivos. P, grupo fosfato; TA, activador transcripcional; TF, factor de transcripción.