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

Farrell, A. S. et al. (2017) MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance. Nature Communications, 8(1), 1728. (doi:10.1038/s41467-017-01967-6) (PMID:29170413) (PMCID:PMC5701042)

[img]
Preview
Text
152690.pdf - Published Version
Available under License Creative Commons Attribution.

3MB

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Murphy, Dr Daniel and Morton, Dr Jennifer and Sansom, Professor Owen
Authors: Farrell, A. S., Joly, M. M., Allen-Petersen, B. L., Worth, P. J., Lanciault, C., Sauer, D., Link, J., Pelz, C., Heiser, L. M., Morton, J. P., Muthalagu, N., Hoffman, M. T., Manning, S. L., Pratt, E. D., Kendsersky, N. D., Egbukichi, N., Amery, T. S., Thoma, M. C., Jenny, Z. P., Rhim, A. D., Murphy, D. J., Sansom, O. J., Crawford, H. C., Sheppard, B. C., and Sears, R. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Nature Communications 8(1):1728
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record