title: Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells.
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.
authors.affiliation: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Enza
authors.initials: E
authors.lastname: Lonardo
authors.forename: Michele
authors.initials: M
authors.lastname: Cioffi
authors.forename: Patricia
authors.initials: P
authors.lastname: Sancho
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Sanchez-Ripoll
authors.forename: Sara Maria
authors.initials: SM
authors.lastname: Trabulo
authors.forename: Jorge
authors.initials: J
authors.lastname: Dorado
authors.forename: Anamaria
authors.initials: A
authors.lastname: Balic
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D015415:Biomarkers; D008687:Metformin