Autophagic perturbation caused by reduced lysosomal activity positively regulates cell competition

Area of Science:

• Cell Biology
• Cancer Research
• Autophagy

Background:

• Cell competition is a mechanism where normal cells eliminate neighboring transformed cells.
• The precise molecular mechanisms driving cell competition remain largely unelucidated.
• Emerging transformed cells pose a threat to tissue homeostasis and integrity.

Purpose of the Study:

• To investigate the role of lysosomal activity and autophagy in cell competition.
• To determine the necessity of autophagosome degradation for the apical extrusion of transformed cells.
• To understand the in vivo consequences of impaired cell competition on tissue integrity.

Main Methods:

• Utilized RAS^G12V/RasV12-transformed cells in co-culture with normal cells.
• Manipulated lysosomal activity and autophagosome formation/degradation.
• Employed a cell competition mouse model to assess in vivo elimination of transformed cells.

Main Results:

• RAS^G12V-transformed cells showed reduced lysosomal activity and autophagosome accumulation.
• Inhibiting autophagy or restoring lysosomal activity impaired the apical extrusion of transformed cells.
• Autophagy-deficient transformed cells were not efficiently eliminated, leading to ductal damage and pancreatitis in mice.

Conclusions:

• Non-degradable autophagosomes are essential mediators of cell competition.
• Autophagy plays a critical role in maintaining tissue homeostasis by eliminating nascent transformed cells.
• Dysfunctional cell competition due to impaired autophagy can lead to pathological conditions like chronic pancreatitis.