Faculty Collaboration Database

Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. Nature 2016 Jun 16;534(7607):407-411

Date

06/10/2016

Pubmed ID

27281208

Pubmed Central ID

PMC4998062

DOI

10.1038/nature17988

Scopus ID

2-s2.0-84976328190 (requires institutional sign-in at Scopus site)   108 Citations

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.

Author List

Fox RG, Lytle NK, Jaquish DV, Park FD, Ito T, Bajaj J, Koechlein CS, Zimdahl B, Yano M, Kopp J, Kritzik M, Sicklick J, Sander M, Grandgenett PM, Hollingsworth MA, Shibata S, Pizzo D, Valasek M, Sasik R, Scadeng M, Okano H, Kim Y, MacLeod AR, Lowy AM, Reya T

Author

Nikki K. Lytle PhD Assistant Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Carcinoma in Situ
Carcinoma, Pancreatic Ductal
Cell Transformation, Neoplastic
Disease Models, Animal
Disease Progression
Drug Resistance, Neoplasm
Female
Gene Deletion
Genes, Reporter
Humans
Male
Mice
Models, Genetic
Molecular Imaging
Neoplastic Cells, Circulating
Nerve Tissue Proteins
Oligonucleotides, Antisense
Pancreatic Neoplasms
RNA-Binding Proteins
Signal Transduction
Survival Rate
Xenograft Model Antitumor Assays