Using fruitflies to help understand the molecular mechanisms of human hereditary diffuse gastric cancer

Abstract

Mutations in the CDH1 gene, which encodes the cell adhesion molecule E-cadherin, are associated with hereditary diffuse gastric cancer in humans. Although most of the CDH1 mutations found are truncating, leading to non-functional E-cadherin, some are missense. These missense E-cadherin mutants result in full-length proteins which, when assayed in cell culture, still retain some biological activity. In order to understand the molecular causes of the malfunction of the E-cadherin missense forms found in patients, we developed a Drosophila model, where the effects of expressing the mutant forms can be studied in vivo (Pereira et al., 2006). Here, we review the results obtained so far, and outline possible ways of exploiting the fly model system to screen for pathways affected by specific E-cadherin missense mutant forms and to identify mechanisms that contribute to tumourigenesis.

E‐cadherin dysfunction in gastric cancer ‐ Cellular consequences, clinical applications and open questions

“…Expression of these mutated proteins in the Drosophila wing epithelium mimicked the in vitro results, both in terms of migration and invasion [134]. A Drosophila approach to screen for novel GC-related genes was recently reported by our group in a background sensitized by E-cadherin mutations [135].…”

CPEB1, a novel gene silenced in gastric cancer: aDrosophilaapproach

“…The screen was designed on the basis of the previously developed Drosophila transgenic model 21 22. The rationale of our screen was that homologues of genes capable of modifying the phenotype caused by misexpression of GC-causing mutants may be part of molecular pathways relevant to GC.…”

“…Here, we used a previously described Drosophila model21 22 to functionally screen for novel GC-related genes, focusing on those showing differential interaction with two causative GC mutations (affecting the extracellular (A634V) or intracellular (V832M) domain of human E-cadherin (hEcad)). This was the way chosen to create a GC-sensitised background.…”

Signalling Pathways in Development and Human Disease: A Drosophila Wing Perspective

“…In addition to genetic searches, Drosophila also permits to recapitulate the biology of particular diseases in vivo systems, an approach that is been applied to the study of tumorigenesis using among other tissues the imaginal discs (Janic et al, 2010). In this manner Drosophila tissues can be used not only to track down the steps leading to tumour initiation, progression and metastasis in vivo, but also to manipulate in genetic mosaics the activity of genes leading to tumoral growth and to assay therapeutic drugs (Kango-Singh and Halder, 2004;Vidal and Cagan, 2006;Jang et al, 2007;Januschke and Gonzalez, 2008;Read et al, 2009;Caldeira et al, 2009;Das and Cagan, 2010;Bina et al, 2010;Wu et al, 2010). This approach is contributing to dissect the effects of tumour-promoting and tumour-suppressing genes in the regulation of proliferation, apoptosis, cell-adhesion, trafficking and cell polarity, and revealed the importance of cellular interactions in the outcome of tumoral progression.…”