• carcinoma

This report describes Drosophila models of epithelial cancer that use overexpression of a fly ortholog of the SRC proto-oncogene or mutations of the C-terminal Src kinase (CSK). 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. CSK downregulates tyrosine kinase activity of the SRC oncoprotein. In Drosophila, the highest-scoring orthologous gene for SRC is Src64B; The highest-scoring ortholog of human CSK in flies is Dmel\Csk. Classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both Dmel\Src64B and Dmel\Csk. For both genes, there are multiple paralogous and orthologous genes in both species. The Drosophila Src42A gene has also been used in a SRC-related disease model; while ortholgous to human SRC, Dmel\Src42A is more closely related to the human Src family genes FRK and FYN.

Overexpression of Src64B results in lethality in the pupal stage; larval imaginal wing discs exhibit significant overgrowth and developmental disorganization. Overexpression of Src64B or knockdown of Csk in the posterior the wing imaginal disc results in epithelial extrusion of cells that move to distant areas from the posterior compartment. Overexpression of Src64B in the wing disc combined with expression of caspase inhibitor BacA\p35 results in overgrowth of the disc.

These systems have been used to characterize modifying and interacting genes; regulators of actin and cytoskeletal remodeling have been characterized in multiple studies (see FBhh0001148). Expression of SSrc64B in small clones has also been characterized: these clones are virtually eliminated from the tissue during development, however, wild-type cells surrounding Src64B-expressing clones significantly overgrow (see FBhh0001074).

The role of SRC has been investigated using expression of a constitutively active allele of Src42A in a portion of the wing disc. This work identified a MAP3K9 Drosophila ortholog, slpr, as playing a downstream role in Src42A-induced overproliferation. This system has been used to identify possible alternative therapeutic options for SRC-related cancers.

[updated Feb. 2021 by FlyBase; FBrf0222196]