This article discusses the origin of pancreatic lesions associated with pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer death worldwide. It is projected to become the second leading cause of cancer death by 2030. Unfortunately, PDAC is often diagnosed at an advanced stage, resulting in a 5-year survival rate of less than 10%. Since the most common precancerous lesions of PDAC are currently not clinically detectable, understanding the mechanisms that lead to their formation and progression is crucial to enabling early diagnosis and more effective therapeutic intervention.

Pancreatic acinar cells are responsible for the production of digestive enzymes. These cells have the ability to regenerate under certain conditions through a process known as “acinar-to-ductal metaplasia” (ADM), which controls their survival, differentiation and proliferation. During this process, acinar cells dedifferentiate and acquire progenitor cell characteristics, allowing them to adapt to their environment. This process is normally reversible, but it can persist in the presence of inflammation, prolonged stress or activation of carcinogenic pathways, leading to the formation of precancerous lesions in the pancreas. We review this process, including the transcription factors and signaling pathways involved. It sheds light on the mechanisms underlying the initiation and progression of precancerous lesions in the pancreas.

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