Acinar to ductal metaplasia (ADM) or acinar cell dedifferentiation is one of the most notable features of chronic pancreatitis. It is also considered the initial step of pancreatic cancer development when oncogenic mutations accumulate. However, its precise mechanism and regulatory pathways remain unclear. This study profiled the transcriptome of dedifferentiated acinar cells from both humans and mice. Differential expression analysis integrated with a systematic literature search revealed several potential regulators (e.g., GDF15, GFRA1, MXRA5, CXCL17), of which the expression pattern over time was validated by qRT-PCR. We also focused on multiple conserved pathways of cell survival, among which SLC7A11 (xCT) is transiently upregulated in both species. The xCT subunit, integral to the cystine/glutamate antiporter system xc-, plays a critical role in cell survival across various cell types. To elucidate its role in acinar dedifferentiation, we employed gene silencing, pharmacological inhibition, and a knock-out mouse model. Acinar cells with diminished xCT function exhibit increased ferroptosis linked to lipid peroxidation. Antioxidants such as N-acetylcysteine and ferroptosis inhibitors like Ferrostatin-1 can mitigate lower glutathione levels and lipid ROS accumulation. Similarly, in mouse acute pancreatitis, xCT prevents lipid peroxidation. Our findings indicate that xCT fuels the glutathione pool and maintains ROS balance during ADM, thereby preventing pancreatic acinar cells from ferroptosis, a form of cell death rarely reported in relation to ADM. Next to xCT, a future and similar comprehensive study of the aforementioned genes could provide valuable insights into the dynamic changes that occur during acinar cell dedifferentiation and pave the way to the discovery of new intervention targets to suppress tumorigenesis in chronic pancreatitis.
Originele taal-2English
Aantal pagina's1
TijdschriftCancer Research
Nummer van het tijdschrift6_supplement
StatusPublished - 15 mrt 2024
EvenementAACR Annual Meeting 2024 - , United States
Duur: 5 apr 202410 apr 2024


Duik in de onderzoeksthema's van 'Abstract 3378: Acinar cell susceptibility for tumor development in the pancreas: Targeting the critical regulators for therapy'. Samen vormen ze een unieke vingerafdruk.

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