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Myc instructs and maintains pancreatic adenocarcinoma phenotype

Nicole M. Sodir, Roderik M. Kortlever, Valentin J.A. Barthet, Luca Pellegrinet, Tania Campos, Steven Kupczak, Lamorna Brown Swigart, Laura Soucek, Mark J. Arends, Trevor D. Littlewood, Gerard I. Evan
doi: https://doi.org/10.1101/556399
Nicole M. Sodir
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
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Roderik M. Kortlever
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
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Valentin J.A. Barthet
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
2Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
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Luca Pellegrinet
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
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Tania Campos
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
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Steven Kupczak
3Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK
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Lamorna Brown Swigart
4Department of Laboratory Medicine, University of California, San Francisco, 2340 Sutter Street, San Francisco, CA 94115, USA
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Laura Soucek
5Vall d’Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain
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Mark J. Arends
6Division of Pathology, Cancer Research UK Edinburgh Centre, University of Edinburgh, Edinburgh, United Kingdom
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Trevor D. Littlewood
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
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Gerard I. Evan
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
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  • For correspondence: gie20@cam.ac.uk
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SUMMARY

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its dismal prognosis and its signature fibroinflammatory phenotype. We show that activation of Myc in PanIN epithelial cells is alone sufficient to instruct and maintain immediate transition of indolent PanINs to PDACs phenotypically identical to the spontaneous human disease. Myc does this by inducing a distinct, tissue-specific ensemble of instructive signals that, together, coordinate changes in multiple, stromal and inflammatory cell types to generate the signature PDAC stroma. We also demonstrate that the Myc PDAC switch is completely reversible and that Myc deactivation immediately triggers meticulous disassembly of both PDAC tumor and stroma. Hence, both the formation and deconstruction of the complex PDAC phenotype may be mediated by a single, reversible molecular switch.

SIGNIFICANCE Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and lacks effective therapies. We show that Myc is a single molecular switch that directly and immediately instructs transition from indolent KRasG12D-induced PanIN to the characteristic complex, multi-cell-type fibroinflammatory and immune-cold PDAC phenotype through the release of a distinct, tissuespecific set of instructive signals. The same combination of KRasG12D and Myc drives a very different phenotype in lung, indicating that the principal phenotypes of adenocarcinomas are dictated by tissue of origin not specific oncogenes. We also show that the Myc switch is immediately and completely reversible: blocking Myc function triggers meticulous disassembly of the entire PDAC tumor-stromal edifice demonstrating that phenotypic complexity is not a barrier to effective treatment of cancers.

Footnotes

  • Lead contact: Gerard I. Evan

Copyright 
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Posted February 21, 2019.
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Myc instructs and maintains pancreatic adenocarcinoma phenotype
Nicole M. Sodir, Roderik M. Kortlever, Valentin J.A. Barthet, Luca Pellegrinet, Tania Campos, Steven Kupczak, Lamorna Brown Swigart, Laura Soucek, Mark J. Arends, Trevor D. Littlewood, Gerard I. Evan
bioRxiv 556399; doi: https://doi.org/10.1101/556399
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Myc instructs and maintains pancreatic adenocarcinoma phenotype
Nicole M. Sodir, Roderik M. Kortlever, Valentin J.A. Barthet, Luca Pellegrinet, Tania Campos, Steven Kupczak, Lamorna Brown Swigart, Laura Soucek, Mark J. Arends, Trevor D. Littlewood, Gerard I. Evan
bioRxiv 556399; doi: https://doi.org/10.1101/556399

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