title: Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.
abstract: Nodal and Activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and Activin regulate self-renewal of pancreatic cancer stem cells. Nodal and Activin were hardly detectable in more differentiated pancreatic cancer cells, while cancer stem cells and stroma-derived pancreatic stellate cells markedly overexpressed Nodal and Activin, but not TGF-β. Knockdown or pharmacological inhibition of the Nodal/Activin receptor Alk4/7 in cancer stem cells virtually abrogated their self-renewal capacity and in vivo tumorigenicity, and reversed the resistance of orthotopically engrafted cancer stem cells to gemcitabine. However, engrafted primary human pancreatic cancer tissue with a substantial stroma showed no response due to limited drug delivery. The addition of a stroma-targeting hedgehog pathway inhibitor enhanced delivery of the Nodal/Activin inhibitor and translated into long-term, progression-free survival. Therefore, inhibition of the Alk4/7 pathway, if combined with hedgehog pathway inhibition and gemcitabine, provides a therapeutic strategy for targeting cancer stem cells.
authors: Clinical Research Programme, Stem Cells and Cancer Group, Spanish National Cancer Research Centre, Madrid 28029, Spain.
authors: Enza
authors: E
authors: Lonardo
authors: Patrick C
authors: PC
authors: Hermann
authors: Maria-Theresa
authors: MT
authors: Mueller
authors: Stephan
authors: S
authors: Huber
authors: Anamaria
authors: A
authors: Balic
authors: Irene
authors: I
authors: Miranda-Lorenzo
authors: Sladjana
authors: S
authors: Zagorac
authors: Sonia
authors: S
authors: Alcala
authors: Iker
authors: I
authors: Rodriguez-Arabaolaza
authors: Juan Carlos
authors: JC
authors: Ramirez
authors: Raul
authors: R
authors: Torres-Ruíz
authors: Elena
authors: E
authors: Garcia
authors: Manuel
authors: M
authors: Hidalgo
authors: David Álvaro
authors: DÁ
authors: Cebrián
authors: Rainer
authors: R
authors: Heuchel
authors: Matthias
authors: M
authors: Löhr
authors: Frank
authors: F
authors: Berger
authors: Peter
authors: P
authors: Bartenstein
authors: Alexandra
authors: A
authors: Aicher
authors: Christopher
authors: C
authors: Heeschen
mesh_terms: D000071916:AC133 Antigen; D028341:Activins / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D005260:Female; D018390:Gene Targeting; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D055457:Nodal Protein / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D055457:Nodal Protein; D010455:Peptides; D028341:Activins