This Drosophila model of epithelial cancer makes use of the fly polarity gene dlg1 and the fly tumor necrosis factor (TNF) family gene egr. Classical loss-of-functions mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\dlg1. RNAi-targeting constructs, alleles caused by insertional mutagenesis, and loss-of-function mutations resulting from imprecise excision of TE insertions have been generated for Dmel\egr.
Loss of apical-basal polarity is an early event in the development of epithelial cancers; genes of the Scribble polarity complex have been used extensively in Drosophila models of epithelial cancer (see FBhh0000586). The fly gene dlg1 is orthologous to four genes in human, DLG1 (a component of the Scribble polarity complex), DLG2, DLG3, and DLG4. Animals homozygous for loss-of-function mutations of Dmel\dlg1 typically die during the larval stage; tumors of the brain and imaginal discs are observed; defects associated with neuromuscular junctions are observed. Knockdown of dlg1 in larval imaginal discs, effected by RNAi, results in apoptosis and an invasion-like phenotype in which cells delaminated and migrated away from the site of origin within the wing disc epithelium; however, most of these animals survive to adulthood, displaying scars along the anterior/posterior boundary of the wing blade, indicating that a mechanism to eliminate the abnormal cells comes into play. (See the human disease model report 'cancer, epithelial, DLG1-related' FBhh0000678).
Tumor necrosis factor (TNF) proteins are transmembrane proteins that can be released from the cell membrane by extracellular proteolytic cleavage; they can act via both autocrine and paracrine signaling. This is a large gene family in human; in Drosophila there is a single TNF family gene, eiger (egr). Animals homozygous for the loss-of-function mutation of egr1 are viable and fertile, with minor feeding and immune response phenotypes. Using the dlg1 model, egr has been found to play a significant role in tumorigenesis in that system. In contrast to the result in wild-type egr animals, in egr1 animals knockdown of dlg1 in larval imaginal discs, effected by RNAi, fails to result in apoptosis, the invasion-like phenotype is more extensive, and all animals die during the pupal stage. Thus presence of wild-type egr is these experiments serves an anti-tumor function.
The role of hemocyte-derived egr has been investigated using overexpression of egr or knockdown by RNAi in hemocytes of dlg1 mutants; tumor size and amount of tumor-related apoptosis in imaginal discs were assayed. The role of hemocytes has also been investigated in related models; see 'cancer, epithelial, TNF-SCRIB-RAS-related' (FBhh0000927).
Multiple physical and genetic interactions have been described for both Dmel\egr and Dmel\dlg1; see below and in the respective gene reports.
[updated Nov. 2018 by FlyBase; FBrf0222196]
DLG1 encodes an essential multidomain scaffolding protein with multiple roles in normal development. It recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells, and may play roles in adherens junction assembly, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. [from Gene Cards, DLG1; 2017.08.01]
The tumor necrosis factor (TNF) superfamily is a protein superfamily of type II transmembrane proteins containing TNF homology domain and forming trimers. Members of this superfamily can be released from the cell membrane by extracellular proteolytic cleavage. TNF proteins are expressed predominantly by immune cells and regulate diverse cell functions, including regulation of immune response and inflammation, but also proliferation, differentiation, apoptosis and embryogenesis. The superfamily contains 19 members that bind to 29 members of TNF receptor superfamily. [https://en.wikipedia.org/wiki/Tumor_necrosis_factor_superfamily] This protein family is also called the TNF ligand family.
TNF proteins can act via both autocrine and paracrine signaling (Caldwell et al., 2014; pubmed:25274725).
HGNC currently lists 18 genes in the Tumor Necrosis Factor Superfamily (https://www.genenames.org/data/genegroup/#!/group/781)
Sole TNF family gene in Drosophila (1 Drosophila to many human); Dmel\egr is most closely related to human EDA, TNFSF13, and TNFSF13B.
Moderate- to high-scoring ortholog of human DLG1, DLG4, DLG2, and DLG3 (1 Drosophila to 4 human). Dmel\dlg1 shares 40-49% identity and 55-63% similarity with the human genes.
