Advanced pancreatic ductal adenocarcinoma (PDA) is almost uniformly fatal due, in large part, to late diagnosis when few effective treatment options are available to patients. Unfortunately, the current standard-of- care chemotherapeutic agents only marginally improve survival time for these patients [1], underscoring the need for an increased understanding of the molecular drivers of pancreatic cancer progression and therapeutic resistance. Cell plasticity is an important driver of intratumoral heterogeneity, which is thought to contribute to drug resistance and disease recurrence in many tumor types [2-4]. Increasing evidence suggests that tumor cells have the capacity to undergo transdifferentiation, conceivably in order to enhance their survival in response to certain selective pressures within their environment. Indeed, numerous studies have demonstrated neuroendocrine (NE) transdifferentiation of prostate tumor cells, particularly in response to androgen- deprivation, in which tumor cells begin to exhibit an NE phenotype and express NE markers, like Synaptophysin and Chromogranin A [5-6]. Although the physiological role of these NE-like cells is unclear, the degree of NE transdifferentiation of tumor cells correlated with tumor progression and poor prognosis in prostate cancer patients. Similar results were found in lung cancer, where NE transdifferentiation was found to be an independent prognostic factor in patients with non-small cell lung cancer [7]. These data suggest that transdifferentiation of tumor cells may contribute to aggressive disease and may be an important mechanism by which tumor cells acquire resistance to therapies, though this process has not been previously described in pancreatic cancer. The c-MYC (MYC) transcription factor is an oncoprotein and potent regulator of many tumorigenic properties, including tumor cell fate. MYC gene amplification or MYC mRNA and/or protein overexpression commonly occurs in pancreatic cancer [8]. Using a novel mouse model of pancreatic cancer, combining physiologic, low-level Myc expression with mutant Kras (KMC mice), we find that deregulated Myc accelerates Kras-driven tumor progression, generating heterogeneous tumors that recapitulate molecular and cellular features of human PDA progression. Interestingly, we detected ductal-cells that express NE markers, like Synaptophysin, suggesting ductal-to-NE conversion. Importantly, similar Synaptophysin/CK-positive lesions are observed in human PDA and correlate with poor outcome. Furthermore, Synaptophysin expression increases upon chemotherapy exposure, suggesting a mechanism of therapeutic resistance. Herein, we will test the hypothesis that NE transdifferentiation of PDA cells drives tumor aggressiveness and resistance to standard-of-care gemcitabine.

Public Health Relevance

/Relevance We have described neuroendocrine (NE) transdifferentiation of pancreatic ductal adenocarcinoma (PDA) cells in both mouse and human PDA, in which tumor cells begin to express NE markers, like Synaptophysin. Importantly, higher percentages of Synaptophysin-positive ductal cells correlate with a shortened disease-free survival and expression is elevated upon chemotherapy exposure, suggesting a mechanism of therapeutic resistance. This study will be the first to examine the role of NE transdifferentiation in PDA progression and chemoresistance and determine what gene pathways control this process, providing unprecedented knowledge and mechanistic understanding of lineage plasticity in pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA213764-02
Application #
9428390
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcguirl, Michele
Project Start
2017-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Genetics
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Farrell, Amy S; Joly, Meghan Morrison; Allen-Petersen, Brittany L et al. (2017) MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance. Nat Commun 8:1728