Protein Kinase D1 Signaling in Cancer Stem Cells with Epithelial-Mesenchymal Plasticity

Abstract

Pancreatic neuroendocrine tumors (pNETs) are extremely diverse and highly vascularized neoplasms that arise from endocrine cells in the pancreas. The pNETs harbor a subpopulation of stem cell-like malignant cells, known as cancer stem cells (CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study, we demonstrate that CSCs in human pNETs co-express protein kinase PKD1 and CD44. We further identify PKD1 signaling as a critical pathway in the control of CSC maintenance in pNET cells. PKD1 signaling regulates the expression of a CSC- and EMT-related gene signature and promotes CSC self-renewal, likely leading to the preservation of a subpopulation of CSCs at an intermediate EMT state. This suggests that the PKD1 signaling pathway may be required for the development of a unique CSC phenotype with plasticity and partial EMT. Given that the signaling networks connected with CSC maintenance and EMT are complex, and extend through multiple levels of regulation, this study provides insight into signaling regulation of CSC plasticity and partial EMT in determining the fate of CSCs. Inhibition of the PKD1 pathway may facilitate the elimination of specific CSC subsets, thereby curbing tumor progression and metastasis.

The Role of CD36 in Cancer Progression and Its Value as a Therapeutic Target

“…For instance, the activation of NF-κB could trigger lipid metabolic rewiring in ovarian cancer cells, thereby activating a transcriptional program that leads to increased CD36 expression, which in turn can be critical for ovarian cancer survival and metastasis [ 14 ]. Interestingly, Protein Kinase D1 (PKD1) is known to be a potent activator of NF-κB [ 46 , 47 ], and it is often aberrantly activated in cancer [ 48 , 49 ]. PKD1 signaling has been demonstrated to mediate the induction of CD36 to facilitate the maintenance of a stem-like phenotype in pancreatic neuroendocrine tumors [ 49 ].…”

“…Interestingly, Protein Kinase D1 (PKD1) is known to be a potent activator of NF-κB [ 46 , 47 ], and it is often aberrantly activated in cancer [ 48 , 49 ]. PKD1 signaling has been demonstrated to mediate the induction of CD36 to facilitate the maintenance of a stem-like phenotype in pancreatic neuroendocrine tumors [ 49 ]. As described below, the transcriptional upregulation of CD36 has been well documented in other cancers.…”