Browsing by Author "Thege, Fredrik I."

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    Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of The Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
    (American Association for Cancer Research, 2023) Sans, Marta; Makino, Yuki; Min, Jimin; Rajapakshe, Kimal I.; Yip-Schneider, Michele; Schmidt, C. Max; Hurd, Mark W.; Burks, Jared K.; Gomez, Javier A.; Thege, Fredrik I.; Fahrmann, Johannes F.; Wolff, Robert A.; Kim, Michael P.; Guerrero, Paola A.; Maitra, Anirban; Surgery, School of Medicine
    Intraductal 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.