and D.S. compartment. Mechanistically, MYC binding is usually 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 usually 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. Introduction Despite focused research efforts, advanced pancreatic ductal adenocarcinoma (PDA) remains almost uniformly fatal due, in large part, to late diagnosis when few effective treatment options are available. Regrettably, current standard of care chemotherapeutic brokers only marginally improve survival time for these patients1, underscoring the need for an increased understanding of the factors responsible for therapeutic resistance. Cell plasticity is usually a key driver of intratumoral phenotypic heterogeneity, which is usually thought to contribute to drug resistance and poor end result in multiple tumor types2C4. Increasing evidence suggests that tumor cells with the capacity for phenotypic plasticity may enter says that allow their survival in response to certain selective pressures within their microenvironment. Indeed, studies indicate that drug Amicarbazone resistance and disease recurrence in prostate adenocarcinoma (PCA) and non-small cell lung malignancy (NSCLC) can involve neuroendocrine transdifferentiation of epithelial tumor cells. For example, in response to androgen-deprivation therapy, prostate tumor cells begin to exhibit a neuroendocrine phenotype and express neuroendocrine markers, such as Synaptophysin (SYP)5 and Chromogranin A6 (ChgA), and the degree of prostate tumor cells with neuroendocrine differentiation features correlates with tumor progression and poor prognosis in patients7, 8. Additionally, therapeutic pressure can drive conversion of NSCLC to high-grade small cell lung malignancy (SCLC) with neuroendocrine morphology9. Thus, the presence of tumor cells with neuroendocrine differentiation DEPC-1 features may be an important mechanism contributing to aggressive disease and therapeutic resistance. A recent publication recognized a subset of pancreatic intraepithelial neoplasia (PanIN)-associated neuroendocrine cells that interacted with sensory neurons to promote PanIN progression and formation10. However, further studies are necessary to determine whether ductal-neuroendocrine lineage plasticity plays a role in PDA aggressiveness and therapeutic resistance. In prostate malignancy, the N-MYC oncoprotein plays a critical role in driving therapy refractory neuroendocrine prostate malignancy (NEPC) and N-MYC overexpression can induce both PCA and NEPC from a common epithelial precursor11C13, 27. Further, c-MYC, in cooperation with Pim1 kinase, can drive invasive prostate carcinoma with neuroendocrine differentiation14. Previous studies have defined Amicarbazone a RAS-regulated signaling pathway that activates c-MYC (MYC) by phosphorylation at Serine 62, which increases its protein half-life and enhances MYCs transcriptional activity15C20. We have exhibited that this post-translationally altered MYC is usually highly Amicarbazone expressed in pancreatic malignancy21. In addition, MYC expression increases upon KRAS expression in the mouse pancreas22. Amicarbazone As PDA is almost universally driven by oncogenic KRAS and given MYCs reported role in neuroendocrine differentiation of PCA, KRAS-induced activation of MYC may contribute to cell lineage plasticity in PDA, that could drive a neuroendocrine differentiation phenotype. Here, we reveal intratumoral cell lineage heterogeneity in human PDA, where we observe Cytokeratin (CK)-positive epithelial tumor cells expressing neuroendocrine markers. We statement that higher Amicarbazone percentages of CK-SYP co-expressing cells are significantly associated with decreased disease-free survival in patients. Tumor cells capable of expressing SYP survive passaging through mice in patient-derived xenograft (PDX) models, supporting their tumor origin. Furthermore, we observe comparable lineage marker heterogeneity in mouse models of PDA, where in vivo lineage tracing experiments indicate the acinar origin of ductal SYP-expressing cells. Using a novel mouse model of PDA combining low-level deregulated MYC expression with mutant KRAS (KMC), we.