Abstract
Pancreatic ductal adenocarcinoma (PDAC) is typically characterized by high chemoresistance and metastatic spread, features mainly attributable to cancer stem cells (CSCs). It is of central interest the characterization of CSCs and, in particular, the study of their metabolic features in order to selectively identify their peculiarities for an efficient therapeutic approach. In this study, CSCs have been obtained by culturing different PDAC cell lines with a specific growth medium. Cells were characterized for the typical stem/mesenchymal properties at short-, medium-, and long-term culture. Metabolomics, proteomics, analysis of oxygen consumption rate in live cells, and the effect of the inhibition of lactate transporter on cell proliferation have been performed to delineate the metabolism of CSCs. We show that gradually de-differentiated pancreatic cancer cells progressively increase the expression of both stem and epithelial-to-mesenchymal transition markers, shift their metabolism from a glycolytic to an oxidative one, and lastly gain a quiescent state. These quiescent stem cells are characterized by high chemo-resistance, clonogenic ability, and metastatic potential. Re-differentiation reverts these features, re-activating their proliferative capacity and glycolytic metabolism, which generally correlates with high aggressiveness. These observations add an important piece of knowledge to the comprehension of the biology of CSCs, whose metabolic plasticity could be exploited for the generation of promising and selective therapeutic approaches for PDAC patients.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and is expected to become the second within the decade [1]
Since it is known that cells harboring stem and mesenchymal features possess a higher migratory ability [27], here we aimed to evaluate the metastatic capacity of the obtained cells by injecting Panc1 cells previously cultured at the three time points in stem-specific medium (SsM) and the relative parental cells in zebrafish (Danio rerio), an animal model that has recently contributed to major insights in the development and progression of PDAC [28,29]
During dormancy, cancer cells become clinically undetectable and resistant to cytotoxic drugs, and their reemergence from dormancy may determine higher aggressiveness [47]. This dormant state is likely to pose a challenge for the metabolic targeting of cancer stem cells (CSCs), as we find that they have low metabolic requirements, very low oxidative metabolism, and are concomitantly resistant to Accumulating evidence indicates that conventional therapies often fail to eradicate carcinoma cells that have entered the stem-state via activation of the epithelial-to-mesenchymal (EMT) program with the consequent tumor relapse [9]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and is expected to become the second within the decade [1]. The understanding of pancreatic cancer biology and genetics has improved, no significant advances in PDAC treatment have been realized in more than 10 years [4], especially due to high chemotherapy and radiation resistance [5]. In a mouse model of PDAC, it has been shown that cellular dissemination leading to metastasis occurs before the formation of an identifiable primary tumor [8]. This behavior has been associated with the presence of circulating pancreatic cells that show a mesenchymal phenotype and express typical stem markers, linking CSCs to epithelial-to-mesenchymal transition (EMT) [8]
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