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  • br Mehralivand S Bednarova S Shih JH et al

    2019-10-14


    32. Mehralivand S, Bednarova S, Shih JH, et al. Prospective evaluation of prostate imaging-reporting and data system version 2 using the interna-tional society of urological pathology prostate cancer grade group sys-tem. J Urol 2017; 198:583–590.
    14 Article
    A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma
    Graphical Abstract Authors
    Nikki K. Lytle, L. Paige Ferguson, Nirakar Rajbhandari, ..., Andrew M. Lowy, Peter D. Adams, Tannishtha Reya
    Correspondence
    treya@ucsd.edu
    In Brief
    Pancreatic cancer stem (−)-Apomorphine co-opt immuno-regulatory pathways, a vulnerability that could be exploited therapeutically by agents currently in trials for autoimmune diseases.
    Highlights
    d Map of PDAC dependencies using RNA-seq, ChIP-seq, and genome-wide CRISPR screening
    d Expression and direct utilization of cytokine and immune signals in PDAC stem cells
    d Nuclear hormone receptor RORg regulates mouse and human pancreatic cancer
    d Pharmacologic blockade of RORg reduces tumor burden and improves survival
    Article
    A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma
    Nikki K. Lytle,1,2,13 L. Paige Ferguson,1,2,13 Nirakar Rajbhandari,1,2 Kathryn Gilroy,3 Raymond G. Fox,1,2 Anagha Deshpande,4 Christian M. Schu¨rch,5 Michael Hamilton,1,2 Neil Robertson,3 Wei Lin,6 Pawan Noel,6 Martin Wartenberg,7 Inti Zlobec,7 Micha Eichmann,7 Jose´ A. Galva´n,7 Eva Karamitopoulou,7 Tami Gilderman,1,2 Lourdes Adriana Esparza,1,2 Yutaka Shima,1,2 Philipp Spahn,8 Randall French,9 Nathan E. Lewis,8 Kathleen M. Fisch,10 Roman Sasik,10 Sara Brin Rosenthal,10 Marcie Kritzik,1,2 Daniel Von Hoff,6 Haiyong Han,6 Trey Ideker,9,11 Aniruddha J. Deshpande,4 Andrew M. Lowy,9,12 Peter D. Adams,3,4 and Tannishtha Reya1,2,9,11,14,* 1Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, CA, USA 2Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA 3Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK 4Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
    5Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, USA
    6Molecular Medicine Division, The Translational Genomics Research Institute, Phoenix, AZ, USA 7Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland 8Department of Pediatrics and the Novo Nordisk Foundation Center for Biosustainability, University of California, San Diego School of Medicine, La Jolla, CA, USA
    9Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA 10Center for Computational Biology and Bioinformatics, University of California, San Diego School of Medicine, La Jolla, CA, USA 11Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA 12Division of Surgical Oncology, Department of Surgery, University of California, San Diego School of Medicine, La Jolla, CA, USA 13These authors contributed equally 14Lead Contact *Correspondence: treya@ucsd.edu
    SUMMARY
    Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipita-tion (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progres-sion. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory sig-nals by pancreatic cancer epithelial cells. In partic-ular, the nuclear hormone receptor retinoic-acid-re-ceptor-related orphan receptor gamma (RORg), known to drive inflammation and T cell differentia-tion, was upregulated during pancreatic cancer pro-gression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients re-vealed that RORg expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of im-muno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be