AbstractsBiology & Animal Science

Modelling colorectal cancer in Drosophila = Establiment d'un model de càncer colorectal a Drosophila

by Òscar Martorell Aleman




Institution: Universitat de Barcelona
Department:
Year: 2014
Keywords: Oncologia; Oncología; Oncology; Càncer colorectal; Cáncer colorectal; Colorectal cancer; Drosòfila; Drosophila; Ciències Experimentals i Matemàtiques
Record ID: 1125760
Full text PDF: http://hdl.handle.net/10803/145376


Abstract

During last decades many researchers have tried to elucidate the different causes of tumour initiation and progression. For this purpose, multiple animal models have been developed to understand the cellular and molecular processes that underlie the cancer disease. The main aim of this thesis has been the generation and characterization of a colorectal cancer model (CRC) in Drosophila melanogaster. With the generation of a CRC in Drosophila, we sought to determine which are those key genes essential during colorectal tumorigenesis. Colorectal cancer (CRC) is one of the most common cancers in the developed countries. The term CRC includes all those malignant lesions that affect the large intestine, the rectum and the appendix. Most of the cases of CRC are sporadic and occur by the accumulation of somatic mutations during the life of the patient. In 1990, Fearon and Vogelstein presented a genetic model to explain how the CRC arise from pre-malign lesions by the accumulation of a set of mutations that would increase progressively the malignancy of the tumour cells (E. Fearon & Vogelstein, 1990). More than 90% of CRC cases have activating mutations in components of the Wnt pathway, and its activation is considered one of the first events in CRC progression. The second more altered signalling pathway is the RTK-RAS pathway, with activating mutations in around 60% of the cases. Mutations in TP53 (64%), PI3K (50%) or TGF-β (27%) pathways are also considered main events for CRC progression (Network, 2012). The generation of a CRC in Drosophila has been possible by the alteration of two main genes involved in human CRC, the Wnt pathway negative regulator Apc and the oncogene Ras. Flies bearing clones mutant for Apc and overexpressing an oncogenic form of Ras (Apc-Ras) develop tumour-like overgrowths in the most anterior part of the adult midgut. These clones show many tumoural characteristics such as high cell proliferation, loss of cell polarity, severe dedifferentiation or expression of migratory markers. In addition, the analysis of the Apc-Ras transcriptome has allowed us to identify hundreds of putative genes involved in tumour progression as well as to confirm the tumour-like behaviour of the Apc-Ras cells. At transcriptional level, Apc-Ras cells present differential expression of many genes encoding signalling proteins and transcription factors that could be crucial for clone development. Interestingly, a RNAi screening has confirmed the essential contribution of some of these genes. In particular, this work has focused in the implication of the TGF-β pathway in Apc-Ras clone progression. TGF-β has emerged as a powerful Apc-Ras clone suppressor and its inactivation is critical for the progression of Apc-Ras clones. Moreover, we have identified the transcription factor Mirror as an essential transcriptional repressor of many of the components of the TGF-β pathway during Apc-Ras progression. Finally, these results have been partially confirmed in in vitro human cell cultures indicating a putative role of IRX proteins…