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

Authors

Marta Sans
Yuki Makino
Jimin Min
Kimal I Rajapakshe
Michele Yip-Schneider
C Max Schmidt
Mark W Hurd
Jared K Burks
Javier A Gomez
Fredrik I Thege
Johannes F Fahrmann
Robert A Wolff
Michael P Kim
Paola A Guerrero
Anirban Maitra

Publication Date

8-4-2023

Journal

Cancer Discovery

Abstract

Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbor 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 re-expression 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.

Keywords

Animals, Mice, Carcinoma, Pancreatic Ductal, Cell Differentiation, Neoplasms, Cystic, Mucinous, and Serous, Pancreas, Pancreatic Intraductal Neoplasms, Pancreatic Neoplasms, Transcriptome, Tumor Microenvironment

Comments

Supplementary Materials

PMID: 37285225