• cancer

This report describes a Drosophila model of cancer that combines an activated mutation in the fly RAS protein Ras85D with mutations of a fly ortholog of the SRC proto-oncogene. The constitutively active Ras85D mutation, Ras85D^V12, is analogous to oncogenic mutations found in human RAS proteins (see FBhh0000474). The SRC gene encodes a non-receptor protein tyrosine kinase that participates in multiple signaling pathways involved in gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, cell migration, and transformation. SRC is overexpressed or activated in multiple human malignancies. The highest-scoring orthologous gene in Drosophila is Src64B, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. A lower-scoring ortholog, Dmel\Src42A has also been used in this system. There are multiple other paralogous and orthologous genes in both species.

Generation of clones of activated Ras85D and/or activated Src64B in the developing eye disc has allowed assessment of cell-cell interactions in this system. Clones of cells overexpressing both Ras85D and Src64B result in marked tumorous overgrowth, but do not exhibit invasive phenotypes. In contrast, when Ras85D^V12 or Src64B overexpressing clones are induced in the same disc in a mosaic manner, both clones frequently invade the ventral nerve cord. Similar results are obtained using Ras85D and Src42A. These cell-cell interactions appear to be mediated via the Notch signaling pathway.

Results using this and the similar RAS-CSK system (FBhh0000664) support the hypothesis that differing levels of SRC activity have different results. In cooperation with RAS, malignant overgrowth is observed specifically when high SRC signaling levels are achieved. It is postulated that SRC activity plays two separable roles during tumor maturation: early low levels of SRC contribute to tumor overgrowth, whereas later high levels of SRC, coupled with other oncogenes such as RAS, lead to invasive migration.

Animals homozygous for an amorphic allele of Dmel\Src64B survive to adulthood; female fertility is severely reduced. When wild-type Src64B is over-expressed in stem cells of the adult gut, intestinal stem cell hyperproliferation and hyperplasia of the adult intestine is observed. Physical and genetic interactions for Dmel\Src64B have been described; see below and in the gene report for Src64B.

Animals homozygous for hypomorphic alleles of Dmel\Src42A die during embryogenesis. When an activated form of Src42A is expressed in stem cells of the adult gut, the resulting phenotype is very similar to that seen for overexpression of Src64B : intestinal stem cell hyperproliferation and hyperplasia of the adult intestine. Dominant-negative forms of both Src64B and Src42A that lack kinase activity produce unexpected phenotypes; a possible explanation is that titration of CSK activity results in a subsequent increase in activity of other negatively regulated CSK targets (see cancer, multiple, RAS-CSK(SRC)-related, FBhh0000664).

[updated Feb. 2022 by FlyBase; FBrf0222196]