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New Cancer Molecular Targets Pilar Navarro

This group belongs to the Associated Unit IMIM-IIBB (June 2018-present), a collaboration agreement between IMIM and the Institute of Biomedical Research of Barcelona (IIBB)-CSIC (https://www.iibb.csic.es/es/research/870). The group is focused on the molecular mechanisms driving cancer onset and progression, with particular emphasis in pancreatic cancer. This tumor is the third-leading cause of cancer-related death in the developed countries and it is one of the most aggressive human tumors. The 5-year patient survival is less than 3%. Currently, there is no useful therapy for this highly malignant tumor and identification of novel molecular targets is an urgent need.

Our group has pioneered research to increase the knowledge about the molecular mechanisms underlying tumor progression and the relevance of tumor-stroma crosstalk in this pathology. Moreover, considering that cancer is a genetic disease caused by changes in gene expression during malignant transformation, we are also interested in deciphering how these genetic changes are regulated. Accordingly, our current objectives are focused in two research lines:

1) Identification of Galectin-1 as a new target for cancer diagnosis and therapy

Previous data from our group identified the molecular mechanisms responsible for the pathological and pro-tumoral effects of tissue-plasminogen activator (tPA), a serin-protease that is overexpressed in several solid tumors (Roda et al. Gastroenterology 2009), leading to the identification for the first time of Galectin-1 (Gal-1) as a tPA receptor. Our further studies, using genetically engineered mouse models demonstrated a key role for Gal-1 in promoting pancreatic carcinogenesis and progression through activation of tumor-microenvironment crosstalk. In particular, Gal-1 favours key steps of cancer progression, as proliferation, angiogenesis, desmoplasia, immune evasion and metaplasia (Martinez-Bosch et al. Cancer Res 2014; Orozco et al. PNAS 2018). Our current research aims to translate our preclinical results into the clinic using different strategies. In collaboration with oncologists and pathologist from Hospital del Mar we are performing retrospective and prospective studies to analyze the use of Gal-1 as a new biomarker for cancer diagnosis and/or predictor of therapy response (Martinez-Bosch et al Oncotarget 2018). Second, our project would enable the development of new therapeutic intervention strategies against cancer by generation of Gal-1 pharmacological inhibitors. Last but not least, given Gal1 overexpression in many different tumors, our data have broader implications in the use of this protein as a novel tumoral molecular target.

2) Establishment of a novel mechanism of regulation of gene expression in cancer (and other pathologies) by RNA translational control

Mounting recent studies have shown that gene expression control goes much further than transcrptional DNA regulation. In particular, RNA translation emerges as a new molecular mechanism responsible for changes in gene expression during cell malignant transformation. CPEB (Cytoplasmic Polyadenylation Element Binding proteins) is a family of RNA binding proteins that mediate regulation of RNA translation by 3'UTR elongation of the polyA tail. Our group has shown that a member of this family, CPEB4, is involved in the cellular reprogramming associated to cancer progression, through activation of RNA translation of a high number of protumoral genes (Ortiz-Zapater et al. Nat Med 2012). More recently, we have also demonstrated that the DEAD-box helicase DDX6, localized in P-bodies and stress granules, mediates a novel mechanism of translational control involving RNA structures within coding sequences that is also conserved in cancer (Jungfleisch et al. Genome Res 2017). These research projects are currently underway in our group.

To pursue these goals we use molecular and cellular biology techniques, cell-based functional assays in vitro, 3D organoid cultures and animal models. Overall, our research will open new avenues for the management of cancer patients, leading to novel target-driven therapies and to the identification of new biomarkers for improved early diagnosis.

Four selected recent publications:

• Martínez-Bosch N, Fernández-Barrena MG, Moreno M, Ortiz-Zapater E, Munné-Collado J, Iglesias M, André S, Gabius HJ, Hwang RF, Poirier F, Navas C, Guerra C, Fernández-Zapico ME, Navarro P. Galectin-1 Drives Pancreatic Carcinogenesis through Stroma Remodeling and Hedgehog Signaling Activation. Cancer Res 2014, 74, 3512-3524.
• Orozco CA, Martinez-Bosch N, Guerrero PE, Vinaixa J, Dalotto-Moreno T, Iglesias M, Moreno M, Djurec M, Poirier F, Gabius HJ, Fernandez-Zapico ME, Hwang RF, Guerra C, Rabinovich GA, Navarro P. Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk. Proc Natl Acad Sci USA 2018, 115, E3769-E3778.
• Martínez-Bosch N, Rodriguez-Vida A, Juanpere N, Lloreta J, Rovira A, Albanell J, Bellmunt J, Navarro P. Galectins in prostate and bladder cancer: tumorigenic roles and clinical opportunities. Nature Rev Urol 2019, 16, 433-445.
• Navarro P, Martínez-Bosch N, Blidner AG, Rabinovich GA. Impact of galectins in resistance to anticancer therapies. Clinical Cancer Res, in press. doi: 10.1158/1078-0432.CCR-18-3870.