Data from MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype

  1. Nicole M. Sodir
  2. Roderik M. Kortlever
  3. Valentin J.A. Barthet
  4. Tania Campos
  5. Luca Pellegrinet
  6. Steven Kupczak
  7. Panayiotis Anastasiou
  8. Lamorna Brown Swigart
  9. Laura Soucek
  10. Mark J. Arends
  11. Trevor D. Littlewood
  12. Gerard I. Evan

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Abstract

<div>Abstract<p>The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of <i>Myc</i> in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells <i>in vivo</i> is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this <i>Myc</i>-driven PDAC switch is completely and immediately reversible: <i>Myc</i> deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible <i>Myc</i> switch.</p>Significance:<p>We show that <i>Myc</i> activation in indolent <i>Kras</i><sup>G12D</sup>-induced PanIN epithelium acts as an immediate pleiotropic switch, triggering tissue-specific signals that instruct all the diverse signature stromal features of spontaneous human PDAC. Subsequent <i>Myc</i> deactivation or inhibition immediately triggers a program that coordinately disassembles PDAC back to PanIN.</p><p><i>See related commentary by English and Sears, p. 495</i>.</p></div>

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