Tumor-promoting and -suppressive roles of autophagy in the same mouse model of BrafV600E-driven lung cancer

Abstract

Although a role of autophagy in cancer development and progression has received increasing appreciation in recent years, there are still significantly uncertain and conflicting results about its tumor-suppressive and -promoting functions, and, more importantly, a lack of understanding of mechanisms underlying these opposing activities. The work presented by Strohecker and colleagues uses an innovative approach to address these challenges by examining the effects of inactivating the key autophagy gene Atg7 at different stages of oncogenic development in a BrafV600E-driven mouse lung cancer model. The authors show that autophagy blockage initially accelerated tumor development, but suppressed tumor progression in later stages, converting adenomas to oncocytomas and increasing mouse survival. Importantly, they identify a critical role of glutamine dependency in the suppression of BrafV600E-induced cancer, thus revealing an important mechanism by which autophagy may promote tumor progression in different cellular contexts.

Figure 1. Differential effect of Atg7 deletion on the early and late stages of BRAF^V600E-driven lung cancer

Autophagy blockage by Atg7 deletion in BRAF^V600E-driven lung tumor cells increased tumor growth at early stage due to failure to remove dysfunctional mitochondria and consequent ROS accumulation. At the late stage, however, impairment of mitochondrial function caused by metabolic stress, and particularly glutamine limitation, becomes a dominant effect in the Atg7-null tumor cells leading to their drastically decreased progression.