• intestinal cancer

A model of intestinal cancer has been developed using the Drosophila Apc and Apc2 genes in combination with the Dmel\Ras85D gene. The Drosophila posterior midgut is closely analogous to the mammalian small intestine; the midgut epithelium is maintained by frequent division of self-renewing intestinal stem cells (ISCs). Somatic clones induced in adult ISCs carrying various combinations of mutations in Apc and Apc2 and an activated form of Ras85D have been characterized. The number of clones carrying both Apc and Apc2 mutants and an activated form of Ras85D (APC-RAS clones) decrease in number over the 4-week period after clone induction, suggesting a mechanism that detects and removes such cells. However, the APC-RAS clones that survive are dramatically enlarged compared to clones bearing the individual mutations; in addition to hyperproliferation, they exhibit disruption of cell differentiation, loss of cell polarity, disorganized organ architecture, and other hallmarks of the adenoma to carcinoma transition in colorectal cancer.

See also the human disease model reports 'familial adenomatous polyposis 1' (FBhh0000135), 'cancer, multiple, RAS-related' (FBhh0000474), 'colorectal cancer, multigenic' (FBhh0000658), and 'cancer, intestinal stem cell models' (FBhh0000767).

The human APC gene is implicated in familial adenomatous polyposis: APC encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. APC has multiple roles in processes that control cell growth and division and is also implicated in several other types of cancer (see MIM:611731). There are two orthologous genes in Drosophila: Dmel\Apc and Dmel\Apc2. There is also a second related human gene, APC2. Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both fly genes. UAS constructs of the human Hsap\APC gene have been introduced into flies; heterologous rescue has not been tested.

The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers and are crucial players in many signaling networks affecting cell cycle progression, growth, migration, cytoskeletal changes, apoptosis, and senescence. Originally defined as oncogenes, the RAS GTPase family includes KRAS (MIM:190070), HRAS (MIM:190020), and NRAS (MIM:164790); mutations in these three genes are among the most common events in human cancers. For KRAS, HRAS and NRAS, there is a single high-scoring ortholog in Drosophila, Ras85D, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. There are multiple other paralogous and orthologous genes in both species. Of the three human RAS GTPase genes, a tagged UAS construct of Hsap\HRAS has been introduced into flies, but has not been characterized.

The constitutively active Ras85D mutation, Ras85D^V12, is analogous to oncogenic mutations found in human RAS proteins. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G12V in the fly Ras85D gene (corresponds to G12V in the human KRAS and HRAS genes).

Animals homozygous for loss-of-function alleles of Dmel\Ras85D die during the larval stage. Most work relevant to cancer has been done with an activated form of the gene, Ras85D^V12. This allele is usually lethal during the pupal stage, with larvae showing tumorous growths; somatic clones of Ras85D^V12 exhibit an overgrowth phenotype in multiple different tissues tested. Many physical and genetic interactions for Dmel\Ras85D have been described; see below and in the gene report for Ras85D.

[updated Oct. 2018 by FlyBase; FBrf0222196]