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

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Universitat de Barcelona. Departament de Genètica

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[cat]  	
Un dels càncers més comuns als països desenvolupats és el càncer colorectal (CRC). El terme CRC inclou totes aquelles lesions tumorals que ocorren a l’intestí gros, el recte i l’apèndix. Aquests càncers ocorren per l’acumulació de mutacions al llarg de la vida del pacient. Més d’un 90% de CRC tenen alteracions a la via de Wnt i la seva activació és considerada un dels primers esdeveniments en la progressió del CRC. La segona via de senyalització més alterada durant la progressió del CRC és la via de RTK-RAS amb alteracions activadores de la via presents en un 60% dels casos de CRC (E. R. Fearon, 2011). L'objectiu principal d'aquesta tesi ha estat establir i caracteritzar un model de CRC a Drosòfila per comprendre millor els processos tumorals i alhora identificar nous gens implicats en la progressió del CRC. Per a generar el model de càncer colorectal a l’intestí mig adult vam induir clons mutants pel gen Apc i sobreexpresant la forma activada de Ras, activant així de forma simultània la via de Wnt i EGFR en les mateixes cèl•lules de l’intestí adult de Drosophila. (clons Apc-Ras). Els clons Apc-Ras mostren característiques tumorals tals com: falta de diferenciació, hiperproliferació, falta de polaritat cel•lular. A més a més els clons Apc-Ras mostren un silenciament transcripcional de la via de senyalització de Dpp. Aquest silenciament és essencial per a la progressió dels clons Apc-Ras degut al paper citostàtic de la via de senyalització Dpp. A més a més aquest treball també ha identificat el factor repressor responsable del silenciament de la via de Dpp, el factor de transcripció Mirror. Mitjançant l’expressió de Mirror les cèl•lules Apc-Ras reprimeixen transcripcionalment diversos components de la via de Dpp i evadeixen així el rol citostàtic d’aquesta via. Finalment aquest treball demostra que les proteïnes IRO (homòlogues a Mirror en humans) podrien exercir un rol de similar a Mirror, reduint la resposta a TGF-β/Dpp per part de les cèl•lules tumorals durant la progressió del CRC

# metadata.dc.description.abstract[].value
[eng] 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 (the human homologues of Mirror) in human CRC progression. This work opens the possibility to study the real implication of many putative genes in an easy genetic model and strongly supports the use of Drosophila as a good animal model system to study molecular and cell cancer biology.

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Tesis Doctorals - Departament - Genètica

# metadata.dc.title[].value
Modelling colorectal cancer in Drosophila = Establiment d'un model de càncer colorectal a Drosophila