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.
Bibliographical noteFunding Information:
Primary pancreatic tumor tissue, resected from patients with informed written patient consent, was supplied by the Brenden-Colson Center for Pancreatic Care (BCCPC). H&E staining was performed by the OHSU Histopathology Shared Resource, and short read sequencing assays (RNA-seq) were performed by the OHSU Massively Parallel Sequencing Shared Resource. Multivariate statistical analysis was performed with assistance from the OHSU Biostatistics Shared Resource. These OHSU Shared Resources are supported by the Knight NCI Cancer Center Support Grant 5P30CA069533. We thank Dr. Joe Gray and Dr. Michel Ouellette for providing cell lines. ASF was supported by a Collins Medical Trust Fund Award, Knight Cancer Institute Career Development Award, and R01 CA196228. RCS was supported by R01s CA196228, CA100855 and CA129040, DOD BC061306, and the Anna Fuller and Brenden-Colson Foundations. B.L.A-P. was supported by NRSA1F32CA192769-01. M.M.J. was supported by NRSA1F32CA213764-01.