title: Conserved mechanisms of tumorigenesis in the Drosophila adult midgut.
abstract: Whereas the series of genetic events leading to colorectal cancer (CRC) have been well established, the precise functions that these alterations play in tumor progression and how they disrupt intestinal homeostasis remain poorly characterized. Activation of the Wnt/Wg signaling pathway by a mutation in the gene APC is the most common trigger for CRC, inducing benign lesions that progress to carcinomas due to the accumulation of other genetic alterations. Among those, Ras mutations drive tumour progression in CRC, as well as in most epithelial cancers. As mammalian and Drosophila's intestines share many similarities, we decided to explore the alterations induced in the Drosophila midgut by the combined activation of the Wnt signaling pathway with gain of function of Ras signaling in the intestinal stem cells. Here we show that compound Apc-Ras clones, but not clones bearing the individual mutations, expand as aggressive intestinal tumor-like outgrowths. These lesions reproduce many of the human CRC hallmarks such as increased proliferation, blockade of cell differentiation and cell polarity and disrupted organ architecture. This process is followed by expression of tumoral markers present in human lesions. Finally, a metabolic behavioral assay shows that these flies suffer a progressive deterioration in intestinal homeostasis, providing a simple readout that could be used in screens for tumor modifiers or therapeutic compounds. Taken together, our results illustrate the conservation of the mechanisms of CRC tumorigenesis in Drosophila, providing an excellent model system to unravel the events that, upon mutation in Apc and Ras, lead to CRC initiation and progression.
authors: Cell and Developmental Biology Program. Institute for Research in Biomedicine, Barcelona, Spain ; Department of Developmental Biology. Institut de Biologia Molecular de Barcelona, Barcelona, Spain.
authors: Òscar
authors: Ò
authors: Martorell
authors: Oncology Program. Institute for Research in Biomedicine, Barcelona, Spain.
authors: Anna
authors: A
authors: Merlos-Suárez
authors: Cell and Developmental Biology Program. Institute for Research in Biomedicine, Barcelona, Spain ; Department of Developmental Biology. Institut de Biologia Molecular de Barcelona, Barcelona, Spain.
authors: Kyra
authors: K
authors: Campbell
authors: Oncology Program. Institute for Research in Biomedicine, Barcelona, Spain.
authors: Francisco M
authors: FM
authors: Barriga
authors: Department of Zoology, University of Cambridge, Cambridge, United Kingdom.
authors: Christo P
authors: CP
authors: Christov
authors: MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom.
authors: Irene
authors: I
authors: Miguel-Aliaga
authors: Oncology Program. Institute for Research in Biomedicine, Barcelona, Spain ; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
authors: Eduard
authors: E
authors: Batlle
authors: Cell and Developmental Biology Program. Institute for Research in Biomedicine, Barcelona, Spain ; Department of Developmental Biology. Institut de Biologia Molecular de Barcelona, Barcelona, Spain.
authors: Jordi
authors: J
authors: Casanova
authors: Cell and Developmental Biology Program. Institute for Research in Biomedicine, Barcelona, Spain ; Department of Developmental Biology. Institut de Biologia Molecular de Barcelona, Barcelona, Spain.
authors: Andreu
authors: A
authors: Casali
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000473:pathology*; D002999:Clone Cells; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000502:physiology*; D041981:Gastrointestinal Tract / Q000473:pathology* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D009857:Oncogenes; D018631:ras Proteins / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D018631:ras Proteins