Mutant KRAS–induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions

Geou Yarh Liou, Heike Döppler, Brian Necela, Brandy Edenfield, Lizhi Zhang, David W. Dawson, Peter Storz

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Desmoplasia and an inflammatory environment are defining features of pancreatic cancer. Unclear is how pancreatic cells that undergo oncogenic transformation can cross-talk with immune cells and how this contributes to the development of pancreatic lesions. Here, we demonstrate that pancreatic acinar cells expressing mutant KRAS can expedite their transformation to a duct-like phenotype by inducing local inflammation. Specifically, we show that KRASG12D induces the expression of intercellular adhesion molecule-1 (ICAM-1), which serves as chemoattractant for macrophages. Infiltrating macrophages amplify the formation of KRASG12D -caused abnormal pancreatic structures by remodeling the extracellular matrix and providing cytokines such as TNF. Depletion of macrophages or treatment with a neutralizing antibody for ICAM-1 in mice expressing oncogenic Kras under an acinar cell–specific promoter resulted in both a decreased formation of abnormal structures and decreased progression of acinar-to-ductal metaplasia to pancreatic intraepithelial neoplastic lesions. Significance: We here show that oncogenic KRAS in pancreatic acinar cells upregulates the expression of ICAM-1 to attract macrophages. Hence, our results reveal a direct cooperative mechanism between oncogenic Kras mutations and the inflammatory environment to drive the initiation of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)52-63
Number of pages12
JournalCancer Discovery
Volume5
Issue number1
DOIs
StatePublished - 2015

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Acinar Cells
Intercellular Adhesion Molecule-1
Macrophages
Pancreatic Neoplasms
Chemotactic Factors
Metaplasia
Neutralizing Antibodies
Extracellular Matrix
Up-Regulation
Cytokines
Inflammation
Phenotype
Mutation

ASJC Scopus subject areas

  • Oncology

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Mutant KRAS–induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. / Liou, Geou Yarh; Döppler, Heike; Necela, Brian; Edenfield, Brandy; Zhang, Lizhi; Dawson, David W.; Storz, Peter.

In: Cancer Discovery, Vol. 5, No. 1, 2015, p. 52-63.

Research output: Contribution to journalArticle

Liou, Geou Yarh ; Döppler, Heike ; Necela, Brian ; Edenfield, Brandy ; Zhang, Lizhi ; Dawson, David W. ; Storz, Peter. / Mutant KRAS–induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. In: Cancer Discovery. 2015 ; Vol. 5, No. 1. pp. 52-63.
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