Novel tools to study aggressive prostate cancer

• Autores: Valentina Maggio
• Directores de la Tesis: Rosanna Paciucci Barzanti (dir. tes.), Juan Morote Robles (codir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2019
• Idioma: español
• Tribunal Calificador de la Tesis: Timothy Thomson Okatsu (presid.), Jaume Farrés Vicén (secret.), Carlo de Carolis (voc.)
• Programa de doctorado: Programa de Doctorado en Bioquímica, Biología Molecular y Biomedicina por la Universidad Autónoma de Barcelona
• Materias:
  • Ciencias de la vida
    • Biología celular
• Enlaces
  • Tesis en acceso abierto en: TESEO
• Resumen

  • Metastatic prostate cancer (PCa) is the third leading cause of death for cancer in Europe and North American men. Gold standard therapy is the androgen deprivation therapy (ADT), although taxanes and newly developed drugs to Androgen Receptor can temporarily bypass the resistance to castration, the Castration Resistant Prostate Cancer (CRPC) is a mortal disease and remains the greatest clinical challenge of prostate cancer. Significant effort has been devoted to discover efficient treatments for these patients and a number of specific inhibitors to some signaling pathways have been identified. However, one important limitation is the very low number of suitable models that reproduce the aggressive disease. In fact, in vivo models able to recapitulate the heterogeneity of prostate tumors are scarce and have several setbacks. Similarly, most in vitro models are derived from metastasis, thus poorly represent the heterogeneity of human prostate tumors. A growing body of evidence suggests that within tumors resides a small population with stem cell-like properties. We hypothesized that ADT can enrich tumors for cancer stem cells (CSCs). Additionally, a successful therapy for PCa would need to be applied at early stages and new markers for the prompt identification of aggressive tumors, or to predict CRPC, together with more specific therapeutic targets are prerequisites. Our previous studies suggested that PTOV1 is a good discriminating marker for HGPIN associated to PCa, that is overexpressed in more aggressive metastatic disease. Furthermore, our functional studies on the role of this protein in resistant tumors suggest that PTOV1 is a good target to eliminate more aggressive cancer cells. The main objective of this thesis is to obtain a simple in vitro model to reproduce the characteristics and behavior of primary prostate tumors to be used in in vitro drug screenings. A second objective is to analyze the mechanisms of the oncogenic protein PTOV1 in the promotion of cancer resistance to chemotherapy. In this work, we established 16 new ex vivo primary prostate tumor cultures from needle biopsies of untreated patients with aggressive cancer. These cultures were characterized for their phenotypes and functional characteristics. In addition, each culture was in parallel treated to derive corresponding Androgen Independent (AI) cultures. These AI primary tumor cultures exhibited in general a reduction of proliferation rate, increase of motility, and resistance to chemotherapy, suggesting that AI cultures are highly plastic and able to overcome the stress caused by chemotherapies. Of note, the treatment with ADT in vitro was associated with an increment of expression of self-renewal markers, suggesting an increase of stemness capacities in the resistant AI cell populations. To establish a model to study CSCs resistance, cells were efficiently selected through a functional protocol based in their ability to form spheres. These spheres were characterized, validated and used to test new drugs.

    Finally, we discovered a new AT-hook like motif within the A domain of the protein PTOV1 with higher affinity to DNA rather than RNA. We have shown that this AT-hook-like motif, through which PTOV1 directly binds to ALDH1A1 and CCNG2 promoters, is necessary to activate the expression of these genes in androgens sensitive cells. PTOV1, ALDH1A1 and CCNG2 high levels are significantly correlated with aggressive metastatic prostate tumors and worst outcome, suggesting that PTOV1 represents a potential target for the treatment of these tumors. These results provide novel tools to targets aggressive prostate tumors.