Genetic analysis of tumour initiation and progression in a Drosophila model of epithelial cancer

Neoplastic overgrowth depends on the cooperation of several mutations ultimately leading to major rearrangements in cellular behaviour. The molecular crosstalk occurring between precancerous and normal cells strongly influences the early steps of the tumourigenic process as well as later stages of the disease. Precancerous cells are often removed by cell death from normal tissues but the mechanisms responsible for such fundamental safeguard processes remain in part elusive. To gain insight into these phenomena I took advantage of the clonal analysis methods available in Drosophila for studying the phenotypes due to loss of function of the neoplastic tumour suppressor lethal giant larvae (lgl). I found that lgl mutant cells growing in wild-type imaginal wing discs are subject to the phenomenon of cell competition and are eliminated by JNK-dependent cell death because they express very low levels of dMyc oncoprotein compared to those in the surrounding tissue. Indeed, in non-competitive backgrounds lgl mutant clones are able to overgrow and upregulate dMyc, overwhelming the neighbouring tissue and forming tumourous masses that display several cancer hallmarks. These phenotypes are completely abolished by reducing dMyc abundance within mutant cells while increasing it in lgl clones growing in a competitive context re-establishes their tumourigenic potential. Similarly, the neoplastic growth observed upon the oncogenic cooperation between lgl mutation and activated Ras/Raf/MAPK signalling was found to be characterised by and dependent on the ability of cancerous cells to upregulate dMyc with respect to the adjacent normal tissue, through both transcriptional and post-transcriptional mechanisms, thereby confirming its key role in lgl-induced tumourigenesis. These results provide first evidence that the dMyc oncoprotein is required in lgl mutant tissue to promote invasive overgrowth in developing and adult epithelial tissues and that dMyc abundance inside versus outside lgl mutant clones plays a key role in driving neoplastic overgrowth.

Regulating Vertical Agreements: A Comparative Law & Economics analysis of Brazil and Europe

This PhD thesis discusses antitrust enforcement of anti-competitive vertical agreements in Europe and in Brazil from an institutional perspective. It considers both the evolution of the legal framework and the application of the existing policies, with the analysis of case studies. The research highlights the main challenges of the current approaches adopted by the competition authorities in these jurisdictions and formulates specific proposals for future improvements. Because the Brazilian competition rules were originally inspired by the European legal framework, this thesis also summarizes the contemporary discussions regarding comparative law and the efficiency of transplanting laws and good practices. In a Law & Economics perspective, vertical agreements have always been a paradoxical topic and constitute one of the most dynamic disputes for antitrust enforcement. The reason for that concern is the fact that those contracts among companies are complex in nature. Taking into account this background, the thesis provides an original analysis of the pro- and anti-competitive effects of vertical agreements, based on the classical literature of Law & Economics. One of the novelties of the research is the extension of the economic analysis of vertical agreements to also consider new forms of contractual abuses in the context of digital markets, such as the contractual restrictions that are being put I practice in e-commerce platforms. The international comparative approach focuses on the Brazilian and European experiences, and opens up a reflection about the policy recommendations applied to several countries with similar economic and institutional realities.