Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma.
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.
Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA.|Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.
Raymond G
RG
Fox
Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA.|Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.
Nikki K
NK
Lytle
Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.|Department of Surgery, Division of Surgical Oncology, University of California San Diego School of Medicine, La Jolla, CA.
Dawn V
DV
Jaquish
Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA.|Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.|Department of Medicine, Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla, CA.
Frederick D
FD
Park
Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA.|Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.
Takahiro
T
Ito
Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA.|Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.
Jeevisha
J
Bajaj
Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA.|Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.
Claire S
CS
Koechlein
Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA.|Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.
Bryan
B
Zimdahl
Department of Physiology, Graduate School of Medicine, Keio University, Keio, Japan.
Masato
M
Yano
Sanford Consortium for Regenerative Medicine, La Jolla, CA.|Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA.
Janel
J
Kopp
Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA.|Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.
Marcie
M
Kritzik
Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.|Department of Surgery, Division of Surgical Oncology, University of California San Diego School of Medicine, La Jolla, CA.
Jason
J
Sicklick
Sanford Consortium for Regenerative Medicine, La Jolla, CA.|Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA.
Maike
M
Sander
Eppley Institute For Research in Cancer and Allied Diseases, Department of Pathology, University of Nebraska Medical Center, Omaha, NE.
Paul M
PM
Grandgenett
Eppley Institute For Research in Cancer and Allied Diseases, Department of Pathology, University of Nebraska Medical Center, Omaha, NE.
Michael A
MA
Hollingsworth
Department of Physiology, Graduate School of Medicine, Keio University, Keio, Japan.
Shinsuke
S
Shibata
Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA.
Donald
D
Pizzo
Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA.
Mark
M
Valasek
Center for Computational Biology and Bioinformatics, University of California San Diego School of Medicine, La Jolla, CA.
Roman
R
Sasik
Department of Radiology, University of California San Diego School of Medicine, La Jolla, CA.
Miriam
M
Scadeng
Department of Physiology, Graduate School of Medicine, Keio University, Keio, Japan.
Hideyuki
H
Okano
Department of Oncology Drug Discovery, Ionis pharmaceuticals, Carlsbad, CA.
Youngsoo
Y
Kim
Department of Oncology Drug Discovery, Ionis pharmaceuticals, Carlsbad, CA.
A Robert
AR
MacLeod
Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.|Department of Surgery, Division of Surgical Oncology, University of California San Diego School of Medicine, La Jolla, CA.
Andrew M
AM
Lowy
Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA.|Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA.
Tannishtha
T
Reya
D000818:Animals; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008957:Models, Genetic; D057054:Molecular Imaging; D009360:Neoplastic Cells, Circulating / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
C491297:MSI1 protein, human; C104786:Msi1h protein, mouse; C499059:Msi2h protein, mouse; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D016601:RNA-Binding Proteins