IMIM - Institut Hospital del Mar d'Investigacions Mèdiques

Molecular Mechanisms of tumorigenesis Pilar Navarro


Molecular mechanisms driving pancreatic cancer progression

The laboratory directed by Pilar Navarro is focused on the molecular mechanisms driving pancreatic cancer progression.

Pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC), is the forth-leading cause of cancer death in the developed countries and it is one of the most aggressive human tumors. The 5-year patient survival is less than 2%. Currently, there is no useful therapy for this highly malignant tumor and identification of novel molecular targets is an urgent need. The plasminogen system and its activators (tPA and uPA) play a critical role in intravascular fibrinolysis as well as in other physiological and pathological processes, such as angiogenesis, inflammation, tissue remodeling, and tumor progression.

Previous data from our laboratory and from other groups have demonstrated that tPA (tissue plasminogen activator) is overexpressed in human and murine pancreatic tumors (Paciucci R et al. FEBS Lett. 1996; Aguilar S et al. Am. J. Pathol. 2004), playing a role in promoting cell invasion, proliferation and angiogenesis (Paciucci R et al. Oncogene 1998; Díaz VM et al. Gastroenterology 2002; Aguilar S et al. Am. J. Pathol. 2004). The role of tPA in the progression of the tumor has also been demonstrated in our group by in vivo studies using murine models of pancreatic cancer and tPA knockout mice. An increase in the survival of Elamyc:tPA–/– mice was observed when compared to Elamyc:tPA+/+ mice, correlating to a decrease in tumoral cell proliferation and angiogenesis (Aguilar S et al. Am. J. Pathol. 2004). Taken together, these data indicate an important role for tPA in pancreatic tumor progression. In order to characterize the molecular mechanisms underlying tPA pro-tumoral functions, our group has been extensively working on characterizing the molecular signaling pathways triggered by tPA and which receptors are mediating these tPA-induced downstream effects in pancreatic cancer. We have demonstrated that, in addition to the well known AnnexinA2 receptor, EGFR and Galectin-1 receptors play a key role in tPA-induced pathological effects in pancreatic tumorigenesis (Ortiz-Zapater E et al. Am. J. Pathol. 2007; Roda O et al. J. Biol. Chem. 2003; Roda O et al. Proteomics 2006; Roda O et al, Gastroenterology 2009).

We are also focused on deciphering the mechanisms involved in the control of altered tPA expression levels in pancreatic cancer. Interestingly, our group has recently demonstrated that tPA expression in PDAC is regulated by the cytoplasmic polyadenylation element binding protein 4 (CPEB4). CPEB4 belongs to the CPEB family of RNA-binding proteins (CPEB1-4) that control RNA translation by binding to specific 3’UTR cis elements in mRNAs and regulate poly(A) elongation. Cytoplasmic polyadenylation was originally discovered as a mechanism to control translation during embryonic development and we have shown that this mechanism also plays a key role during reprogramming of gene expression in tumoral cells. We have found that CPEB4 is overexpressed in pancreatic cancer, as well as in glioblastoma, supporting tumor growth, angiogenesis and invasion through the translational activation of hundreds of mRNAs, including tPA (Ortiz-Zapater E et al. Nat. Med. 2011).

Our current objectives are focused in two main research lines:

  • Characterize the importance of Gal-1 in pancreatic cancer using in vivo animal models.
  • Characterize the role of the CPEB family in pancreatic cancer and other tumors.

Finally, although our major research is focused in cancer, we are also interested in the role of tPA during neurodegeneration and Alzheimer’s disease (AD) pathogenesis. We have reported that tPA is overexpressed in AD patients’ brain, where it colocalizes with senile plaques and triggers neurotoxicity (Medina M et al. EMBO J. 2005; Montolio M et al. J. Med. Chem. 2012), as well as glial inflammation (Pineda D et al. Glia 2012).

From left to right and from top to bottom: Joan Gibert, Mireia Moreno, Héctor Anta, Pilar Navarro, Neus Martínez, Núria Gutiérrez and Tamara Arjona.

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