Differential role of Interleukin-1 and Interleukin-6 in K-Ras-driven pancreatic carcinoma undergoing mesenchymal transition

Imran Siddiqui, Marco Erreni, Mohammad Azhar Kamal, Chiara Porta, Federica Marchesi, Samantha Pesce, Fabio Pasqualini, Silvia Schiarea, Chiara Chiabrando, Alberto Mantovani, Paola Allavena

Research output: Contribution to journalArticle

Abstract

K-Ras mutations are a hallmark of human pancreatic adenocarcinoma (PDAC) and epithelial-mesenchymal-transition (EMT) is a driver of progression. Oncogenic K-Ras causes the constitutive activation of NF-kB and the switch-on of an inflammatory program, which further fuels NF-kB and STAT3 activation. In this study we investigated how inflammatory pathways triggered by oncogenic K-Ras are regulated in human pancreatic cancer cells with distict epithelial or mesenchymal phenotype. Our results demonstrate that in cells with epithelial features, K-Ras driven inflammation is under the control of IL-1, while in cells undergoing EMT, is IL-1 independent. In pancreatic tumor cells with EMT phenotype, treatment with IL-1R antagonist (Anakinra) did not inhibit inflammatory cytokine production and tumor growth in mice. In these cells IL-6 is actively transcribed by the EMT transcription factor TWIST. Targeting of mesenchymal pancreatic tumors in vivo with anti-IL-6RmAb (RoActemra) successfully decreased tumor growth in immunodeficient mice, inhibited the inflammatory stroma and NF-kB-p65 and STAT3 phosphorylation in cancer cells. The results confirm that IL-1 is an important driver of inflammation in epithelial pancreatic tumors; however, tumor cells undergoing EMT will likely escape IL-1R inhibition, as IL-6 is continuously transcribed by TWIST. These findings have implications for the rational targeting of inflammatory pathways in human pancreatic cancer.

Original languageEnglish
Article numbere1388485
JournalOncoImmunology
Volume7
Issue number2
DOIs
Publication statusPublished - Feb 1 2018

Keywords

  • Cancer Immunotherapy
  • EMT
  • Inflammation
  • Oncogene
  • Therapeutic Antibodies

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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