The role of cell competition in tumour initiation and progression in Drosophila melanogaster

• Autores: Luna Laura Ballesteros Arias
• Directores de la Tesis: Ginés Morata (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2016
• Idioma: español
• Tribunal Calificador de la Tesis: José Fernández Piqueras (presid.), Manuel Calleja Requena (secret.), Francisco X Real (voc.), Miguel Torres Sánchez (voc.), Eduardo Moreno Lampaya (voc.)
• Programa de doctorado: Programa Oficial de Doctorado en Bioquímica, Biología Molecular, Biomedicina y Biotecnología (Biociencias Moleculares)
• Calificación: Sobresaliente Cum Laude
• Materias:
  • Ciencias de la vida
    • Biología animal (zoología)
      • Desarrollo animal
      • Genética animal
      • Patología animal
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • During the life of a multicellular organism mutations may arise spontaneously or due to environmental stress. The acquisition of a survival or a proliferative advantage by mutant cells could drive the appearance of tumours. These events are likely to be frequent in humans, taking into account the great number of cell divisions that take place, the mutation rate and the large amount of oncogenes and tumour suppressor genes. However, during the life of an individual, tumours rarely appear.

    A phenomenon was described in Drosophila that supervises the quality of tissues, termed cell competition. Its principal function is the identification and subsequent elimination of aberrant cells that may appear during development. This surveillance function includes the detection of potentially oncogenic cells. Thus cell competition may play an important role in eliminating tumours before they are clinically detectable.

    We have analysed the role of cell competition in Drosophila tumorigenesis. We show that cell competition eliminates oncogenic cells in which the endocytic machinery is impaired and with high tumorigenic potential. In addition, we find that if oncogenic cells form a sufficiently large group, they create a protective microenvironment that allows the growth of the tumour.

    We describe how cell competition occurring at the confrontation of tumour- and non-tumour cells can promote the growth of the tumour once a protective microenvironment has been created. Interestingly, cell competition causes mitogenic signalling from apoptotic cells that in turn results in overproliferation. We show that under these circumstances non-tumour cells are recruited to the tumour thus stimulating further growth.

    We have also used a different tumour model to analyse the mitogenic signalling from apoptotic cells. We have so far tested the role of a particular signal, Wingless, and the mechanism by which it can induce extra proliferation of adjacent cells. We propose that Wingless spread is needed to induce overgrowths when there is a continuous signalling from apoptotic cells both through the stimulation of proliferation and through the generation of novel foci of wingless-expressing cells. This phenomenon could account for the overgrowthsassociated to cell competition in our tumour model. Our finding that apoptotic cells secrete proliferative signals responsible for tumour growth suggests that some of the current anti-tumour treatments administered to human patients may be counterproductive.

    Finally we have performed a screen to identify candidate cellular functions or elements that could be involved in the specific detection of tumour cells by cell competition.