Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells

Sandra Valle, Sonia Alcalá, Laura Martin-Hijano, Pablo Cabezas-Sáinz, Diego Navarro, Edurne Ramos Muñoz, Lourdes Yuste, Kanishka Tiwary, Karolin Walter, Laura Ruiz-Cañas, Marta Alonso-Nocelo, Juan A. Rubiolo, Emilio González-Arnay, Christopher Heeschen, Laura Garcia-Bermejo, Patrick C. Hermann, Laura Sánchez, Patricia Sancho, Miguel Ángel Fernández-Moreno () and Bruno Sainz ()
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Sandra Valle: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Sonia Alcalá: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Laura Martin-Hijano: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Pablo Cabezas-Sáinz: Universidad de Santiago de Compostela
Diego Navarro: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Edurne Ramos Muñoz: Biomarkers and Therapeutic Targets Group - IRYCIS
Lourdes Yuste: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Kanishka Tiwary: Ulm University
Karolin Walter: Ulm University
Laura Ruiz-Cañas: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Marta Alonso-Nocelo: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Juan A. Rubiolo: Universidad de Santiago de Compostela
Emilio González-Arnay: Universidad Autónoma de Madrid (UAM)
Christopher Heeschen: Spanish National Cancer Research Centre (CNIO)
Laura Garcia-Bermejo: Biomarkers and Therapeutic Targets Group - IRYCIS
Patrick C. Hermann: Ulm University
Laura Sánchez: Universidad de Santiago de Compostela
Patricia Sancho: IIS Aragón
Miguel Ángel Fernández-Moreno: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM
Bruno Sainz: Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: Abstract Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7–9%. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Herein, we describe a 2D in vitro system for long-term enrichment of pancreatic CSCs that is amenable to biological and CSC-specific studies. By changing the carbon source from glucose to galactose in vitro, we force PDAC cells to utilize OXPHOS, resulting in enrichment of CSCs defined by increased CSC biomarker and pluripotency gene expression, greater tumorigenic potential, induced but reversible quiescence, increased OXPHOS activity, enhanced invasiveness, and upregulated immune evasion properties. This CSC enrichment method can facilitate the discovery of new CSC-specific hallmarks for future development into targets for PDAC-based therapies.

Date: 2020
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DOI: 10.1038/s41467-020-18954-z

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