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). A model of intestinal cancer has been developed using an activated form of the Drosophila RAS gene Ras85D. The constitutively active Ras85D mutation, Ras85DV12, is analogous to oncogenic mutations found in human RAS proteins.
Expression of Ras85DV12 targeted to ISCs in the adult fly results in stem cell hyperproliferation and intestinal dysplasia. Tumor growth correlates with an expansion of tracheal cell branching, similar to increased angiogenesis observed for human cancers. Ras85DV12 expression in renal and nephric stem cells (RNSCs) and hindgut intestinal stem cells (HISCs) has also been characterized.
Several studies using these systems address the role of specific lipids within the plasma membrane and the impact of diet and interacting genes on lipid usage within transformed stem cells. Using animals with Ras85DV12 expression targeted to ISCs, supplementing the diet with long-chain n-3 fatty acids (n-3 PUFA) has been found to reduce the hyperproliferation phenotype; the distribution of RAS-signaling nanoclusters in the plasma membrane has been characterized in the Ras85DV12 animals without and without n-3 PUFA dietary supplementation.
Knockdown of genes encoding components of the coat protein complex I is thought to attenuate the lipolysis pathway; in animals carrying these mutations plus Ras85DV12, normal and transformed intestinal stem cells are killed, but differentiated cells are not.
See the human disease model report 'cancer, multiple, RAS-related' (FBhh0000474) for additional information concerning the Ras85DV12 cancer model.
[updated Jul. 2021 by FlyBase; FBrf0222196]