Autophagic perturbation caused by reduced lysosomal activity positively regulates cell competition.

Newly emerging transformed epithelial cells are recognized and apically removed by surrounding normal cells through a biological event termed "cell competition". However, little is known about the mechanisms underlying this process. In a recent study, we describe that RAS G12V /RasV12-transformed cells surrounded by normal cells exhibit decreased lysosomal activity accompanied with accumulation of autophagosomes. Restoration of low lysosomal activity or inhibition of autophagosome formation significantly antagonizes apical extrusion of RAS G12V cells, suggesting that non-degradable autophagosomes are required for cell competition. Notably, analysis of a cell competition mouse model demonstrates that macroautophagy/autophagy-ablated RAS G12V cells are less readily eliminated by cell competition, and remaining transformed cells destroy ductal integrity, leading to chronic pancreatitis. Thus, our findings illuminate a critical role for non-degradable autophagosomes in cell competition and reveal a homeostasis-preserving role of autophagy upon emergence of transformed cells.