Autophagy suppresses tumor progression by limiting chromosomal instability

TLDR

Autophagy normally supports cell survival under metabolic stress, yet loss of key autophagy genes such as beclin1 increases metabolic vulnerability and promotes tumorigenesis. The study seeks to elucidate the mechanism by which loss of this survival pathway paradoxically enhances tumor growth. Compromised autophagy induces metabolic failure, DNA damage, gene amplification, and aneuploidy, leading to chromosomal instability that drives tumor progression, highlighting autophagy’s role in genome protection and its therapeutic potential.

Abstract

Autophagy is a bulk degradation process that promotes survival under metabolic stress, but it can also be a means of cell death if executed to completion. Monoallelic loss of the essential autophagy gene beclin1 causes susceptibility to metabolic stress, but also promotes tumorigenesis. This raises the paradox that the loss of a survival pathway enhances tumor growth, where the exact mechanism is not known. Here, we show that compromised autophagy promoted chromosome instability. Failure to sustain metabolism through autophagy was associated with increased DNA damage, gene amplification, and aneuploidy, and this genomic instability may promote tumorigenesis. Thus, autophagy maintains metabolism and survival during metabolic stress that serves to protect the genome, providing an explanation for how the loss of a survival pathway leads to tumor progression. Identification of this novel role of autophagy may be important for rational chemotherapy and therapeutic exploitation of autophagy inducers as potential chemopreventive agents.