Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells

PLoS One. 2013 Oct 18;8(10):e76518. doi: 10.1371/journal.pone.0076518. eCollection 2013.

Abstract

Pancreatic ductal adenocarcinomas contain a subset of exclusively tumorigenic cancer stem cells (CSCs), which are capable of repopulating the entire heterogeneous cancer cell populations and are highly resistant to standard chemotherapy. Here we demonstrate that metformin selectively ablated pancreatic CSCs as evidenced by diminished expression of pluripotency-associated genes and CSC-associated surface markers. Subsequently, the ability of metformin-treated CSCs to clonally expand in vitro was irreversibly abrogated by inducing apoptosis. In contrast, non-CSCs preferentially responded by cell cycle arrest, but were not eliminated by metformin treatment. Mechanistically, metformin increased reactive oxygen species production in CSC and reduced their mitochondrial transmembrane potential. The subsequent induction of lethal energy crisis in CSCs was independent of AMPK/mTOR. Finally, in primary cancer tissue xenograft models metformin effectively reduced tumor burden and prevented disease progression; if combined with a stroma-targeting smoothened inhibitor for enhanced tissue penetration, while gemcitabine actually appeared dispensable.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / metabolism
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Disease Progression
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Metformin / pharmacology*
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism

Substances

  • Biomarkers
  • Metformin

Grant support

The research was supported by the ERC Advanced Investigator Grant (Pa-CSC 233460), European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement n°256974, the Subdirección General de Evaluación y Fomento de la Investigación, Fondo de Investigación Sanitaria (PS09/02129), and the Programa Nacional de Internacionalización de la I+D, Subprogramma: FCCI 2009 (PLE2009–0105; both Ministerio de Ciencia e Innovación, Spain). E.L. is supported by the Roche Postdoctoral Fellowship Program. M.C. is supported by the La Caixa Predoctoral Fellowship Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.