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Open AccessArticle

Progressively De-Differentiated Pancreatic Cancer Cells Shift from Glycolysis to Oxidative Metabolism and Gain a Quiescent Stem State

1
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy
2
Department of Ecological and Biological Sciences, University of Tuscia, 01100 Viterbo, Italy
3
Department of Biotechnology, University of Verona, 37134 Verona, Italy
4
Department of Biomedical Sciences, University of Padova, 35122 Padova, Italy
5
Research Center LURM (Interdepartmental Laboratory of Medical Research), University of Verona, 37134 Verona, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2020, 9(7), 1572; https://doi.org/10.3390/cells9071572
Received: 18 May 2020 / Revised: 25 June 2020 / Accepted: 26 June 2020 / Published: 28 June 2020
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. View Full-Text
Keywords: cancer stem cells; pancreatic ductal adenocarcinoma; cancer metabolism; quiescence; metabolic plasticity cancer stem cells; pancreatic ductal adenocarcinoma; cancer metabolism; quiescence; metabolic plasticity
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Ambrosini, G.; Dalla Pozza, E.; Fanelli, G.; Di Carlo, C.; Vettori, A.; Cannino, G.; Cavallini, C.; Carmona-Carmona, C.A.; Brandi, J.; Rinalducci, S.; Scupoli, M.T.; Rasola, A.; Cecconi, D.; Palmieri, M.; Dando, I. Progressively De-Differentiated Pancreatic Cancer Cells Shift from Glycolysis to Oxidative Metabolism and Gain a Quiescent Stem State. Cells 2020, 9, 1572.

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