Despite numerous advances in our understanding of pancreatic ductal adenocarcinoma (PDA) genetics and biology, this disease is expected to become the second leading cause of cancer-related U.S. deaths within the next few years. Incomplete understanding of how it arises precludes development of early detection and interception strategies to improve therapeutic outcomes. Acinar to ductal metaplasia involving genesis of tuft cells is one early step in PDA formation, but their functional significance has remained obscure due to their rarity and a lack of methods and relevant animal models for their molecular and functional analysis. Here, we show that deletion of tuft cell master regulator Pou2f3 eliminates pancreatic tuft cells and increases fibrosis, alters immune cell activation, and accelerates disease progression. We demonstrate that tuft cell expression of the prostaglandin D 2 synthase Hpgds restrains pancreatic disease progression in early stages by inhibiting stromal activation. Analyses of human data sets are consistent with mouse studies. We propose that tuft cells and, by inference, the associated metaplastic lesions, play a protective role early in pancreatic tumorigenesis. Significance:We find that tuft cell formation in response to oncogenic Kras is protective and restrains tumorigenesis through local production of anti-inflammatory substances, including paracrine prostaglandin D 2 signaling to the stroma. Our findings establish tuft cells as a metaplasia-induced tumor suppressive cell type. Introduction:Chemical or mechanical injury of the pancreas results in a cell state-switching event termed acinar to ductal metaplasia (ADM) where digestive enzyme producing acinar cells dedifferentiate into proliferative ductal-like cells to restore pancreas homeostasis. This process is perturbed during neoplastic progression, where, in mouse models, initiating Kras mutations prevent tissue healing and, instead, ADM is thought to progress to pancreatic intraepithelial neoplasia (PanIN) and then pancreatic ductal adenocarcinoma (PDA). This is an example of Dvorak's thesis, which states that cancer represents the ever-healing wound (1).The profound difference between the normal healing process and the perturbed response engendered by oncogene activation raises the important question of whether key cell types that result from ADM impact cancer progression. Here, we investigate the role of tuft cells as they appear in response to oncogeneinduced metaplasia in a number of cancers of human significance including lung, stomach, intestine, and pancreas (2-6).Tuft cells are solitary chemosensory cells found throughout the hollow organs of the respiratory and digestive tracts. They are readily identified by their striking morphological features, including long, blunt microvilli, deep actin rootlets, and an extensive tubulovesicular system in the supranuclear cytoplasm (7).Their expression of taste, neuronal, and inflammatory cell signaling factors is thought to enable monitoring of intraluminal homeostasis and to achieve loc...