Sans, MartaMakino, YukiMin, JiminRajapakshe, Kimal I.Yip-Schneider, MicheleSchmidt, C. MaxHurd, Mark W.Burks, Jared K.Gomez, Javier A.Thege, Fredrik I.Fahrmann, Johannes F.Wolff, Robert A.Kim, Michael P.Guerrero, Paola A.Maitra, Anirban2024-06-112024-06-112023Sans M, Makino Y, Min J, et al. Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential. Cancer Discov. 2023;13(8):1844-1861. doi:10.1158/2159-8290.CD-22-1200https://hdl.handle.net/1805/41412Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbors a gastric foveolar-type epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of IPMNs, followed by orthogonal and cross-species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric cell identity in low-grade IPMNs. Loss of NKX6-2 expression is a consistent feature of IPMN progression, while reexpression of Nkx6-2 in murine IPMN lines recapitulates the aforementioned gastric transcriptional program and glandular morphology. Our study identifies NKX6-2 as a previously unknown transcription factor driving indolent gastric differentiation in IPMN pathogenesis.en-USPublisher PolicyPancreatic ductal carcinomaCell differentiationPancreasTumor microenvironmentArticle