Image based detection and targeting of therapy resistance in pancreatic adenocarcinoma

Pancreatic intraepithelial neoplasia (PanIN) is a premalignant 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 in...

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Main Authors:	Fox, Raymond G., Lytle, Nikki K., Jaquish, Dawn V., Park, Frederick D., Ito, Takahiro, Bajaj, Jeevisha, Koechlein, Claire S., Zimdahl, Bryan, Yano, Masato, Kopp, Janel, Kritzik, Marcie, Sicklick, Jason, Sander, Maike, Grandgenett, Paul M., Hollingsworth, Michael A., Shibata, Shinsuke, Pizzo, Donald, Valasek, Mark, Sasik, Roman, Scadeng, Miriam, Okano, Hideyuki, Kim, Youngsoo, MacLeod, A. Robert, Lowy, Andrew M., Reya, Tannishtha
Format:	Online
Language:	English
Published:	2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998062/

id	pubmed-4998062
recordtype	oai_dc
spelling	pubmed-49980622016-12-06 Image based detection and targeting of therapy resistance in pancreatic adenocarcinoma Fox, Raymond G. Lytle, Nikki K. Jaquish, Dawn V. Park, Frederick D. Ito, Takahiro Bajaj, Jeevisha Koechlein, Claire S. Zimdahl, Bryan Yano, Masato Kopp, Janel Kritzik, Marcie Sicklick, Jason Sander, Maike Grandgenett, Paul M. Hollingsworth, Michael A. Shibata, Shinsuke Pizzo, Donald Valasek, Mark Sasik, Roman Scadeng, Miriam Okano, Hideyuki Kim, Youngsoo MacLeod, A. Robert Lowy, Andrew M. Reya, Tannishtha Article Pancreatic intraepithelial neoplasia (PanIN) is a premalignant 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 SMAD42-4. To date, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavor. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression in both genetic models and 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 PanIN progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbor the capacity to propagate adenocarcinoma, are enriched in circulating tumor 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 PanIN progression to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumors, 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 tumor 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 signaling as a central regulator of pancreatic cancer. 2016-06-06 /pmc/articles/PMC4998062/ /pubmed/27281208 http://dx.doi.org/10.1038/nature17988 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Fox, Raymond G. Lytle, Nikki K. Jaquish, Dawn V. Park, Frederick D. Ito, Takahiro Bajaj, Jeevisha Koechlein, Claire S. Zimdahl, Bryan Yano, Masato Kopp, Janel Kritzik, Marcie Sicklick, Jason Sander, Maike Grandgenett, Paul M. Hollingsworth, Michael A. Shibata, Shinsuke Pizzo, Donald Valasek, Mark Sasik, Roman Scadeng, Miriam Okano, Hideyuki Kim, Youngsoo MacLeod, A. Robert Lowy, Andrew M. Reya, Tannishtha
spellingShingle	Fox, Raymond G. Lytle, Nikki K. Jaquish, Dawn V. Park, Frederick D. Ito, Takahiro Bajaj, Jeevisha Koechlein, Claire S. Zimdahl, Bryan Yano, Masato Kopp, Janel Kritzik, Marcie Sicklick, Jason Sander, Maike Grandgenett, Paul M. Hollingsworth, Michael A. Shibata, Shinsuke Pizzo, Donald Valasek, Mark Sasik, Roman Scadeng, Miriam Okano, Hideyuki Kim, Youngsoo MacLeod, A. Robert Lowy, Andrew M. Reya, Tannishtha Image based detection and targeting of therapy resistance in pancreatic adenocarcinoma
author_facet	Fox, Raymond G. Lytle, Nikki K. Jaquish, Dawn V. Park, Frederick D. Ito, Takahiro Bajaj, Jeevisha Koechlein, Claire S. Zimdahl, Bryan Yano, Masato Kopp, Janel Kritzik, Marcie Sicklick, Jason Sander, Maike Grandgenett, Paul M. Hollingsworth, Michael A. Shibata, Shinsuke Pizzo, Donald Valasek, Mark Sasik, Roman Scadeng, Miriam Okano, Hideyuki Kim, Youngsoo MacLeod, A. Robert Lowy, Andrew M. Reya, Tannishtha
author_sort	Fox, Raymond G.
title	Image based detection and targeting of therapy resistance in pancreatic adenocarcinoma
title_short	Image based detection and targeting of therapy resistance in pancreatic adenocarcinoma
title_full	Image based detection and targeting of therapy resistance in pancreatic adenocarcinoma
title_fullStr	Image based detection and targeting of therapy resistance in pancreatic adenocarcinoma
title_full_unstemmed	Image based detection and targeting of therapy resistance in pancreatic adenocarcinoma
title_sort	image based detection and targeting of therapy resistance in pancreatic adenocarcinoma
description	Pancreatic intraepithelial neoplasia (PanIN) is a premalignant 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 SMAD42-4. To date, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavor. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression in both genetic models and 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 PanIN progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbor the capacity to propagate adenocarcinoma, are enriched in circulating tumor 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 PanIN progression to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumors, 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 tumor 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 signaling as a central regulator of pancreatic cancer.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998062/
_version_	1613635017639985152

Image based detection and targeting of therapy resistance in pancreatic adenocarcinoma

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