Abstract B45: Embryogenesis meets tumorigenesis: Nodal/activin signaling drives self-renewal and invasiveness of pancreatic cancer stem cells

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/or Activin regulate self-renewal and invasiveness of pancreatic cancer stem cells. While their expression was hardly detectable in differentiated pancreatic cancer cells, cancer stem cells demonstrate a drastic upregulation for Nodal and, to a lesser extent, Activin while TGF-β remained unchanged. Pancreatic stellate cells as the putative microenvironment for cancer stem cells produce very high amounts of Activin, and, to a lesser extent, Nodal. Knockdown and pharmacological inhibition of their common receptor Alk4/7 both significantly, but reversibly reduced cancer stem cell self-renewal / invasiveness and cancer stem cells subsequently became sensitive to gemcitabine. Importantly, while orthotopically engrafted primary human cancer cell suspensions were highly responsive to Nodal/Activin inhibition plus gemcitabine, engrafted primary human pancreatic cancer tissue xenografts containing massive stroma did not slow down tumor progression. Intriguingly, the addition of a stroma-targeting sonic hedgehog pathway inhibitor resulted in enhanced delivery of the Nodal/Activin inhibitor and gemcitabine, respectively, and translated into long-term disease stabilization. Therefore, modulation of the Alk4/7 pathway, if combined with hedgehog pathway inhibition and gemcitabine, provides a novel therapeutic strategy for targeted elimination of cancer stem cells in order to overcome their resistance towards gemcitabine. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B45.