Autophagy in the Tumor or in the Host: Which Plays a Greater Supportive Role?

Abstract

<b/> Autophagy has been identified as a potential therapeutic target in pancreatic ductal adenocarcinoma, one of the most lethal cancers, with few therapeutic options. Yang and colleagues successfully created a genetically engineered mouse model focused on the autophagy gene Atg4b that allows the study of therapeutic autophagy inhibition in fully formed tumors. Using this tool, they demonstrated that selective autophagy inhibition in either the tumor cells, normal host cells, or both suppresses tumor growth. Cancer Discov; 8(3); 266-8. ©2018 AACRSee related article by Yang et al., p. 276.

Figure 1

A, Targeting Atg4b in the tumor and in the host. ATG4B cleaves LC3 to form LC3-I. Then, ATG7 along with a cascade of other proteins conjugates LC3-I with phosphatidylethanolamine (PE) to form LC3-II, which is required for cargo recruitment and autophagosome maturation. The autophago-some fuses the lysosome to enable cargo degradation and finally the cargo constituents are recycled. Dominant-negative ATG4B (ATG4B^DN) protein sequesters free LC3, preventing autophagosome maturation. B, Expression of Atg4b^DN in pancreatic cells, which harbor mutations in Kras and Trp53, produces tumor growth suppression but is also associated with acinar–ductal metaplasia that disrupts normal exocrine pancreas function. In pancreatic cells that harbor wild-type (WT) Kras and Trp53 and expression of Atg4b^DN, no metaplasia or functional pancreas impairment is observed. C, Schematic representation of results of an orthotopic pancreatic cancer model in which Atg4b^DN can be expressed in tumor cells, the entire body or both. Tumor growth at early and late time points. ✓, intact autophagy; ✘, deficient autophagy.