Metformin Targets the Metabolic Achilles Heel of Human Pancreatic Cancer Stem Cells

Enza Lonardo, Michele Cioffi, Patricia Sancho, Yolanda Sanchez-Ripoll, Sara Maria Trabulo, Jorge Dorado, Anamaria Balic, Manuel Hidalgo, Christopher Heeschen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere76518
JournalPloS one
Volume8
Issue number10
DOIs
StatePublished - Oct 18 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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