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Autophagy driven by VPS34 enables differentiated cell plasticity and cancer initiation

Ramos-Delgado, F.; Shalhoub, H.; Guyon, C.; Handschin, C.; Cerapio-Arroyo, P.; DAngelo, R.; Therville, N.; Villard, A.; Cayron, C.; Valle, C.; Sarot, E.; Dussere, N.; Di-Luoffo, M.; Rebours, V.; Couvelard, A.; Joffre, C.; de Oliveira, H.; Dufresne, M.; Thibault, B.; Guillermet-Guibert, J.

2025-05-07 pathology
10.1101/2025.05.02.651270 bioRxiv
Show abstract

Differentiated cell plasticity and autophagy are fundamental mechanisms of tissue repair. To investigate their integration to maintain tissue homeostasis, we developed a unique model in which VPS34, the highly conserved class III PI3K that promotes autophagic flux, was inactivated in pancreatic exocrine cells, recognised study models. Using scRNAseq, we found that VPS34-null acinar cells evolved towards a transcriptional identity present at low levels in mouse and human pancreas. Functionally, it unexpectedly prevented transdifferentiation, chronic pancreatitis and precancer initiation triggered by stressors. Mechanistically, the newly differentiated cell state was less susceptible to cancer promotion by oncogenic KRAS, through reduced class I PI3K and increased lysosomal degradation of pro-inflammatory REG3A. This result opens the so far unreachable possibility of strategies for protection from environmentally induced cancer initiation.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.