Integrative proteomic analysis of ovarian cancer: understanding tumour physiology and predicting response to treatment

• Autores: Melissa Bradbury Lobato
• Directores de la Tesis: Eduard Sabidó Aguadé (dir. tes.), Anna Santamaría Margalef (codir. tes.)
• Lectura: En la Universitat Pompeu Fabra ( España ) en 2020
• Idioma: español
• Tribunal Calificador de la Tesis: Jesper V. Olsen (presid.), Gemma Mancebo Moreno (secret.), Emilio Lecona Sagrado (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Pompeu Fabra
• Materias:
  • Química
    • Química analítica
      • Espectroscopia de masas
  • Ciencias de la vida
    • Biología molecular
  • Ciencias médicas
    • Patología
      • Oncología
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• Resumen

  • High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer. It is characterised by presenting defects in the homologous recombination repair, most frequently associated to BRCA1 mutations. Although most patients will initially respond to first-line chemotherapy with platinum-based agents, up to a quarter will be resistant to treatment. In this thesis we have aimed, firstly, to advance in the understanding of HGSC tumour physiology and its dependence on BRCA1 and, secondly, to identify a protein signature able to discriminate between chemotherapy resistant and sensitive patients. To this intent, in the first part of the thesis, we have performed a multi-layered proteomic characterization of patient-derived ovarian tissues, which has revealed the importance of both ubiquitination and phosphorylation layers of regulation in modulating key cellular processes in HGSC, their dependency on BRCA1 and the identification of BRCA1 substrates responsible for driving ubiquitination signalling. In the second part of the thesis, using discovery and targeted proteomics in HGSC tissues, we have identified a protein signature able to discriminate between chemotherapy resistant and sensitive patients at the time of cancer diagnosis. Collectively, we have performed a comprehensive molecular characterization of HGSC that provides a groundwork for future mechanistic-based studies and the development of new targeted therapies in ovarian cancer. In addition, we advance in the optimization of therapeutic decision making through the identification of a promising protein signature able to predict response to chemotherapy.