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 resistance1. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2, 3, 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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We are grateful to I. Verma, M. Karin, and D. Cheresh for advice and comments on the manuscript, A. Luo and T. Wang for technical support, G. Yeo for advice on Msi targeting, K. Jenne for advice on MRI imaging, N. Patel and P. Mischel for reagents and experimental advice, and E. O’Conner and K. Marquez for cell sorting. R.F. is a recipient of a California Institute for Regenerative Medicine interdisciplinary stem cell training program fellowship and received support from T32 HL086344 and T32 CA009523, C.K. received support from T32 GM007752, N.K.L. received support from T32 GM007752 and a National Research Service Award F31 CA206416, J.L.K. received support from National Institutes of Health (NIH)-F32CA136124 and an Advanced Postdoctoral Fellowship from the Juvenile Diabetes Research Foundation, and B.Z. received support from T32 GM007184-33 (Duke University). F.P. is a recipient of a California Institute for Regenerative Medicine interdisciplinary stem cell training program fellowship and the University of California San Diego Clinical and Translational Research Institute KL2 Award. T.I. is the recipient of a California Institute for Regenerative Medicine interdisciplinary stem cell training program fellowship, J.B. is supported by a postdoctoral fellowship from National Cancer Center, and T.R. was supported in part by a Leukemia and Lymphoma Society Scholar Award. P.M.G. and M.A.H. are supported by a Specialized Program of Research Excellence (SPORE) in Pancreatic Cancer, CA127297, a TMEN Tumor Microenvironment Network U54, a National Cancer Institute Cancer Center Support Grant P30 CA36727, and an Early Detection Research Network (EDRN) U01 CA111294, M.Sa. is supported by NIH DK078803 and NIH CA194839, J.K.S. is supported by NIH K08CA168999, R.S. is supported by the Clinical and Translational Research Institute (CTRI) grant UL1TR001442, and A.M.L. is supported by donations from Ride the Point. This work was also supported by CA155620 to A.M.L., DK63031, HL097767, DP1 CA174422, and R35 CA197699 to T.R., and CA186043 to A.M.L. and T.R.
Extended data figures
4D view of Msi2 reporter+ pancreatic cancer cells within tumor mass. VE-cadherin (magenta), Hoechst (blue) and Msi2 reporter (green).
3-D projection of MRI image from control mouse with normal pancreas.
3-D projection of MRI image from WT-KPf/fC mouse (11 weeks)
3-D projection of MRI image from Msi1-/--KPf/fC mouse (11 weeks)
3-D projection of MRI image from WT-KPf/fC mouse, (13 weeks)
3-D projection of MRI image from Msi2-/--KPf/fC mouse, (13 weeks)
About this article
Journal of Hematology & Oncology (2017)