MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance

Amy S. Farrell, Meghan Morrison Joly, Brittany L. Allen-Petersen, Patrick J. Worth, Christian Lanciault, David Sauer, Jason Link, Carl Pelz, Laura M. Heiser, Jennifer P. Morton, Nathiya Muthalagu, Megan T. Hoffman, Sara L. Manning, Erica D. Pratt, Nicholas D. Kendsersky, Nkolika Egbukichi, Taylor S. Amery, Mary C. Thoma, Zina P. Jenny, Andrew D. Rhim, Daniel J. Murphy, Owen J. Sansom, Howard C. Crawford, Brett C. Sheppard and Rosalie C. Sears ()
Additional contact information
Amy S. Farrell: Oregon Health and Science University
Meghan Morrison Joly: Oregon Health and Science University
Brittany L. Allen-Petersen: Oregon Health and Science University
Patrick J. Worth: Oregon Health and Science University
Christian Lanciault: Oregon Health and Science University
David Sauer: Oregon Health and Science University
Jason Link: Oregon Health and Science University
Carl Pelz: Oregon Health and Science University
Laura M. Heiser: Oregon Health and Science University
Jennifer P. Morton: Beatson Institute
Nathiya Muthalagu: Beatson Institute
Megan T. Hoffman: University of Michigan
Sara L. Manning: Hepatology and Nutrition and Zayed Center for Pancreatic Cancer Research, University of Texas M.D. Anderson Cancer Center, Unit 1466
Erica D. Pratt: Hepatology and Nutrition and Zayed Center for Pancreatic Cancer Research, University of Texas M.D. Anderson Cancer Center, Unit 1466
Nicholas D. Kendsersky: Oregon Health and Science University
Nkolika Egbukichi: Oregon Health and Science University
Taylor S. Amery: Oregon Health and Science University
Mary C. Thoma: Oregon Health and Science University
Zina P. Jenny: Oregon Health and Science University
Andrew D. Rhim: Hepatology and Nutrition and Zayed Center for Pancreatic Cancer Research, University of Texas M.D. Anderson Cancer Center, Unit 1466
Daniel J. Murphy: Beatson Institute
Owen J. Sansom: Beatson Institute
Howard C. Crawford: University of Michigan
Brett C. Sheppard: Oregon Health and Science University
Rosalie C. Sears: Oregon Health and Science University

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Intratumoral phenotypic heterogeneity has been described in many tumor types, where it can contribute to drug resistance and disease recurrence. We analyzed ductal and neuroendocrine markers in pancreatic ductal adenocarcinoma, revealing heterogeneous expression of the neuroendocrine marker Synaptophysin within ductal lesions. Higher percentages of Cytokeratin-Synaptophysin dual positive tumor cells correlate with shortened disease-free survival. We observe similar lineage marker heterogeneity in mouse models of pancreatic ductal adenocarcinoma, where lineage tracing indicates that Cytokeratin-Synaptophysin dual positive cells arise from the exocrine compartment. Mechanistically, MYC binding is enriched at neuroendocrine genes in mouse tumor cells and loss of MYC reduces ductal-neuroendocrine lineage heterogeneity, while deregulated MYC expression in KRAS mutant mice increases this phenotype. Neuroendocrine marker expression is associated with chemoresistance and reducing MYC levels decreases gemcitabine-induced neuroendocrine marker expression and increases chemosensitivity. Altogether, we demonstrate that MYC facilitates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma, contributing to poor survival and chemoresistance.

Date: 2017
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DOI: 10.1038/s41467-017-01967-6

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