• carcinoma

The constitutively active Drosophila RAS mutation Ras85D^V12 is analogous to oncogenic mutations found in human RAS proteins. Several studies in flies have addressed questions concerning the role of autophagy in RAS-driven tumorigenesis. See the human disease model report 'cancer, multiple, RAS-related' (FBhh0000474) for additional information concerning Ras85D^V12 cancer models.

A genetic screen for loss-of-function mutations that enhance a hyperplastic phenotype of Ras85D^V12 identified multiple genes involved in the autophagy pathway, including Atg8a (ortholog of human GABARAP and GABARAPL1) and Atg9 (ortholog of human ATG9A and ATG9B), Atg1 (ortholog of human ULK1 and ULK2). In subsequent experiments, knockdown of almost all tested genes involved in the autophagy pathway enhanced Ras85D^V12-induced overgrowth, including nSyb (ortholog of human VAMP2, VAMP1, and VAMP3).

Results in flies were extended to a human system. Using available RNAseq data from The Cancer Genome Atlas, expression of autophagy genes was assessed for human pancreatic ductal adenocarcinoma (PAAD), since incidence of KRAS-activating mutations in this tumor type is very high. The analysis showed that lower expression of several core autophagy genes, including GABARAP and VAMP2, correlates with oncogenic KRAS mutations and poor prognosis in this pancreatic cancer.

In work using multiple different cancer models in flies (including RAS-driven and NOTCH-driven) to assess alterations in autophagy, different results were obtained in different systems. It was concluded that differing influences of autophagy on cell and tissue growth may depend on both oncogenic signal and cell type.

[updated May 2019 by FlyBase; FBrf0222196]