PT  - JOURNAL ARTICLE
AU  - Nicole M. Sodir
AU  - Roderik M. Kortlever
AU  - Valentin J.A. Barthet
AU  - Luca Pellegrinet
AU  - Tania Campos
AU  - Steven Kupczak
AU  - Lamorna Brown Swigart
AU  - Laura Soucek
AU  - Mark J. Arends
AU  - Trevor D. Littlewood
AU  - Gerard I. Evan
TI  - Myc instructs and maintains pancreatic adenocarcinoma phenotype
AID  - 10.1101/556399
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 556399
4099  - http://biorxiv.org/content/early/2019/02/21/556399.short
4100  - http://biorxiv.org/content/early/2019/02/21/556399.full
AB  - 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.