From Drosophila to Humans: MYC-Mediated Clone Competition as an Evolutionary Trait of Tumor Progression

• Main Author: Di Giacomo, Simone <1984>
• Other Authors: Pession, Annalisa
• Format: Doctoral Thesis
• Language: en
• Published: Alma Mater Studiorum - Università di Bologna 2016
• Subjects: MED/04 Patologia generale
• Online Access: http://amsdottorato.unibo.it/7598/

Cell competition describes the result of a mechanism of fitness comparison undertaken by cells inhabiting the same tissue, that leads to the elimination of the weakest cells and, in the physiology, to the formation of a homogeneous organ. Over the years, many molecules have been identified that are involved in cell competition and among them MYC oncoprotein: from Drosophila to mammals, cell populations characterised by higher expression of MYC induce apoptotic death of the neighbours, allowing the fittest to acquire an advantage in space occupancy. My work defined the presence of markers of MYC-mediated cell competition in primary and secondary human carcinomas and demonstrated through experiments in human cancer cell lines that MYC modulation is per se sufficient to induce competitive behaviours in both genetically distant and identical cells. Noteworthy, MYC under-regulation in the fittest cell line is sufficient to undermine its competitive status, suggesting a role for MYC-mediated cell competition in the selective growth of tumour clones and, as a consequence, in cancer evolution. In addition, I was able to demonstrate a functional cooperation between MYC and p53 in this phenomenon. The data obtained in the Drosophila model, where MYC over-expressing and MYC knock-down clones have been induced within a growing tumour, suggest that MYC-mediated cell competition is normally at work in these malignant cells, and it shapes cancer evolution through the elimination of the less fit cells (with lower levels of MYC) and the expansion of the most performant ones (with higher levels of MYC), demonstrating an evolutionary role played in defining the composition and the size of the final mass.