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

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

doi:10.1158/2159-8290.CD-22-1200

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

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

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4 Scopus citations

Abstract

Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most com-mon 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.

Original language	English (US)
Pages (from-to)	1844-1861
Number of pages	18
Journal	Cancer discovery
Volume	13
Issue number	8
DOIs	https://doi.org/10.1158/2159-8290.CD-22-1200
State	Published - Aug 1 2023

ASJC Scopus subject areas

Oncology

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10.1158/2159-8290.CD-22-1200

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Sans, M., Makino, Y., Min, J., Rajapakshe, K. I., Yip-Schneider, M., Schmidt, C. M., Hurd, M. W., Burks, J. K., Gomez, J. A., Thege, F. I., Fahrmann, J. F., Wolff, R. A., Kim, M. P., Guerrero, P. A., & Maitra, A. (2023). Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential. Cancer discovery, 13(8), 1844-1861. https://doi.org/10.1158/2159-8290.CD-22-1200

Sans, M, Makino, Y, Min, J , Rajapakshe, KI, Yip-Schneider, M, Schmidt, CM, Hurd, MW, Burks, JK, Gomez, JA, Thege, FI , Fahrmann, JF , Wolff, RA , Kim, MP , Guerrero, PA & Maitra, A 2023, 'Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential', Cancer discovery, vol. 13, no. 8, pp. 1844-1861. https://doi.org/10.1158/2159-8290.CD-22-1200

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

abstract = "Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most com-mon 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.",

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

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doi = "10.1158/2159-8290.CD-22-1200",

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AU - Sans, Marta

AU - Makino, Yuki

AU - Min, Jimin

AU - Rajapakshe, Kimal I.

AU - Yip-Schneider, Michele

AU - Schmidt, C. Max

AU - Hurd, Mark W.

AU - Burks, Jared K.

AU - Gomez, Javier A.

AU - Thege, Fredrik I.

AU - Fahrmann, Johannes F.

AU - Wolff, Robert A.

AU - Kim, Michael P.

AU - Guerrero, Paola A.

AU - Maitra, Anirban

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N2 - Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most com-mon 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.

AB - Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most com-mon 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.

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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

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