Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the pancreas but the transcriptional program underlying these changes is incompletely understood. The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1aCreER;Prdm3flox/flox mice) in the context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In Prdm3-deficient mice, KrasG12D-driven preneoplastic lesions were more abundant and progressed to high-grade precancerous lesions more rapidly. This is consistent with our observations that low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed that pathways involved in inflammatory response and Hif-1 signaling were significantly upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 favors the maintenance of acinar cell homeostasis through modulation of their response to inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive role during PDAC initiation.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy in pancreas and the third leading cause of cancer-related deaths in US1
We first characterized the expression of PRDM3 and its relevance to pancreatic cancer prognosis by analyzing a cohort of 94 patients who were diagnosed with PDAC and received surgical resection without preoperative chemotherapy
We found that PRDM3 was strongly expressed in precancerous pancreatic intraepithelial neoplasia (PanIN) lesions (Fig. 1c–c’) and well-differentiated PDAC from patients (Fig. 1d–d’), while moderately to poorly differentiated cancer cells showed little to no staining of PRDM3 (Fig. 1e–e’, f–f’, Table 1)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy in pancreas and the third leading cause of cancer-related deaths in US1. Ye et al Cell Death and Disease (2020)11:187 presence of pancreatitis[7,8], while, in humans, induction of chronic inflammation is a common character in many known risk factors for pancreatic cancer including diabetes, pancreatitis, alcohol consumption and tobacco use[9]. Using siRNA-mediated knockdown of PRDM3 in PK-8 pancreatic cancer cells, Tanaka and colleagues showed that PRDM3 promotes pancreatic cancer cell proliferation and migration through the inhibition of a KRAS suppressor miR-9614. Despite this characterization of the effects of PRDM3 inhibition in pancreatic tumor cells ex vivo, the role of PRDM3 during tumor initiation from acinar cells in vivo is unclear
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