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Nature. 2016 Jun 16;534(7607):407-411. doi: 10.1038/nature17988. Epub 2016 Jun 6.

Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma.

Author information

1
Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA.
2
Sanford Consortium for Regenerative Medicine, La Jolla, CA.
3
Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.
4
Department of Surgery, Division of Surgical Oncology, University of California San Diego School of Medicine, La Jolla, CA.
5
Department of Medicine, Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla, CA.
6
Department of Physiology, Graduate School of Medicine, Keio University, Keio, Japan.
7
Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA.
8
Eppley Institute For Research in Cancer and Allied Diseases, Department of Pathology, University of Nebraska Medical Center, Omaha, NE.
9
Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA.
10
Center for Computational Biology and Bioinformatics, University of California San Diego School of Medicine, La Jolla, CA.
11
Department of Radiology, University of California San Diego School of Medicine, La Jolla, CA.
12
Department of Oncology Drug Discovery, Ionis pharmaceuticals, Carlsbad, CA.
#
Contributed equally

Abstract

Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2-4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signalling as a central regulator of pancreatic cancer.

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PMID:
27281208
PMCID:
PMC4998062
DOI:
10.1038/nature17988
[Indexed for MEDLINE]
Free PMC Article

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