Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential

Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fi de 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 identifi es NKX6-2 as a previously unknown transcription factor driving indolent gastric differentiation in IPMN pathogenesis.SIGNIFICANCE: Identifi cation of the molecular features driving IPMN development and differentiation is critical to prevent cancer progression and enhance risk stratifi cation. We used spatial profi ling to characterize the epithelium and microenvironment of IPMN, which revealed a previously unknown link between NKX6-2 and gastric differentiation, the latter associated with indolent biological potential.See related commentary by Ben-Shmuel and Scherz-Shouval, p. 1768.

Automated summary

Intraductal papillary mucinous neoplasms (IPMN) of the pancreas with gastric foveolar-type epithelium and low-grade mucinous neoplasms are linked to high-grade dysplasia and cancer. The study identified the transcription factor NKX6-2 as a key driver of gastric cell identity in low-grade IPMNs. Understanding the molecular features of IPMN development and differentiation is critical for preventing cancer progression.