Physiological levels of Kras(G12D) are sufficient to induce pancreatic intraepithelial neoplasias (PanINs); the mechanisms that drive PanIN progression are unknown. Here, we establish that, in addition to oncogenic Kras(G12D), IL-6 transsignaling-dependent activation of Stat3/Socs3 is required to promote PanIN progression and pancreatic ductal adenocarcinoma (PDAC). Myeloid compartment induces Stat3 activation by secreting IL-6; consequently, IL-6 transsignaling activates Stat3 in the pancreas. Using genetic tools, we show that inactivation of IL-6 transsignaling or Stat3 inhibits PanIN progression and reduces the development of PDAC. Aberrant activation of Stat3 through homozygous deletion of Socs3 in the pancreas accelerates PanIN progression and PDAC development. Our data describe the involvement of IL-6 transsignaling/Stat3/Socs3 in PanIN progression and PDAC development.
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