Acinar to ductal metaplasia (ADM) is considered the main origin of pancreatic pre-neoplastic lesions that eventually develop into pancreatic ductal adenocarcinoma (PDA). ADM could be a decisive step during tumorigenesis, selecting plastic cells for a more aggressive subsequent tumorigenesis. Now, researchers from the Vanderbilt University School of Medicine Basic Sciences and the Salk Institute for Biological Studies show that acinar cells in the pancreas form new cell types to mitigate injury but are then susceptible to cancerous mutations.

Their findings are published in the journal Gastroenterology in an article titled, “Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury,” and led by Kathy DelGiorno, PhD, assistant professor of cell and developmental biology at the School of Medicine Basic Sciences, and Geoffrey Wahl, PhD, professor in the Gene Expression Laboratory and holder of the Daniel and Martina Lewis chair at the Salk Institute.

“ADM occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma,” the researchers wrote. “The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression.”

The researchers combined single-cell RNA sequencing, ultrastructural microscopy, genetically engineered models, and patient samples to identify the cell types that form in response to pancreatic injury.

From this approach, “we compared our dataset to published datasets of gastric injury, oncogene-induced pancreatic neoplasia, and human pancreatitis to identify conserved processes across species and organ systems,” said DelGiorno.

“ScRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia,” the researchers wrote. “Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs).

“Under conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse. KrasG12D expression is sufficient to drive neoplasia when targeted to injury-induced ADM populations and offers an alternative origin for tumorigenesis. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases.”

“We hope to co-opt and/or target these processes for the benefit of patients needing treatment for pancreatitis and cancer,” DelGiorno said.