PKD-1 Signaling Is Required for the Maintenance of CSCs with Epithelial-mesenchymal Plasticity in Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (pNETs) are extremely heterogeneous and highly vascularized neoplasms that arise from endocrine cells in the pancreas. pNETs harbor a subpopulation of stem cell-like cancer cells (cancer stem cells/CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study we demonstrated that CSCs in human pNETs co-expressed PKD-1 and CD44. We further identified PKD-1 signaling as a critical pathway in the regulation of CSC maintenance in pNET cells. PKD-1 signaling regulated the expression of a CSC-related gene signature and promoted CSC self-renewal. Intriguingly, pharmacological or genetic disruption of PKD-1 signaling in human pNET cells impaired lysophosphatidic acid-induced expression of genes associated with epithelial to mesenchymal transition (EMT), specifically E-cadherin and vimentin. This study indicates that PKD-1 signaling is essential for the maintenance of a subpopulation of CSCs in pNETs at an intermediate state along the epithelial-mesenchymal spectrum, thereby leading to a CSC phenotype with plasticity and partial EMT. Inhibiting the PKD-1 pathway may facilitate the elimination of CSC subpopulations to curb pNET progression, therapeutic resistance and metastasis. Given that the signaling networks associated with CSC maintenance and EMT are complex and extend across multiple levels of gene regulation, this study provides insight into signaling regulation of partial EMT in determining CSC fate and aids in developing potential therapeutic strategies that target different subsets of CSCs in a variety of cancers.