Pancreatic tuft cells are produced by the potentially oncogenic process of acinar-to-ductal metaplasia (ADM), but what part these cells play in pancreatic tumorigenesis was largely unknown. A new study now suggests that tuft cells have a protective role in the progression of pancreatic ductal adenocarcinoma (PDAC).
Chemosensory tuft cells are found throughout the digestive tract, with limited functional data indicating multifaceted roles in sensing and responding to inflammatory conditions. Previous work by author Kathleen DelGiorno found that tuft cells form in the pancreas by ADM, but their physiological effects were undetermined. ADM and its role in pancreatic cancer was a focus of research by author Geoffrey Wahl, so a collaborative study was formed.
Credit: Scanning electron microscopy image of a tuft cell. Image courtesy of G. Wahl and K. DelGiorno.
The researchers used several methods to determine the functional role of tuft cells in pancreatic tumorigenesis. “We used genetically engineered mouse models lacking tuft cells to study how pancreatic tumours form in their absence, and we used single-cell sequencing and histopathology to evaluate the effects of tuft cell deletion on the neoplastic stroma,” says DelGiorno. The investigators found that tuft cell ablation in mouse models of PDAC accelerated tumorigenesis. “Pancreatic tuft cells act to restrain tumorigenesis rather than seed or drive cancer formation,” explains DelGiorno.
Using small cell number RNA-sequencing and metabolic profiling to examine tuft cell mechanisms, a role for eicosanoid secretion in curbing activation of the tumour stoma was highlighted. “While some eicosanoids have been described to be pro-tumorigenic, we found that pancreatic neoplasia exhibit high levels of anti-tumorigenic prostaglandin D2 to which tuft cells substantially contribute,” reports Wahl, adding that tuft cells might also produce other paracrine factors that modulate tumour progression.
Finally, the investigators also examined tissue samples from patients with PDAC (n = 197) and its precursor lesions (n = 45). They found gene expression signatures associated with tuft cells were higher in precursor lesions than PDAC, supporting the hypothesis that tuft cells suppress disease progression.
“tuft cell ablation in mouse models of PDAC accelerated tumorigenesis”
“In the course of these studies we identified a number of other potential tuft cell mechanisms of disease suppression worth evaluating,” says DelGiorno. “We are also interested in understanding how conditions known to predispose to pancreatic and other cancers, such as obesity and inflammation, induce cell state-switching events,” adds Wahl.
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Dickson, I. Tuft cells restrain PDAC progression.
Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-020-00358-5