Science and Research

Mutant KRAS promotes malignant pleural effusion formation

Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition.

  • Agalioti, T.
  • Giannou, A. D.
  • Krontira, A. C.
  • Kanellakis, N. I.
  • Kati, D.
  • Vreka, M.
  • Pepe, M.
  • Spella, M.
  • Lilis, I.
  • Zazara, D. E.
  • Nikolouli, E.
  • Spiropoulou, N.
  • Papadakis, A.
  • Papadia, K.
  • Voulgaridis, A.
  • Harokopos, V.
  • Stamou, P.
  • Meiners, S.
  • Eickelberg, O.
  • Snyder, L. A.
  • Antimisiaris, S. G.
  • Kardamakis, D.
  • Psallidas, I.
  • Marazioti, A.
  • Stathopoulos, G. T.


  • Adenocarcinoma/drug therapy/*genetics/pathology
  • Animals
  • Antineoplastic Agents/*pharmacology/therapeutic use
  • Benzimidazoles/pharmacology/therapeutic use
  • Cell Line, Tumor
  • Chemokine CCL2/antagonists & inhibitors/metabolism/secretion
  • Chickens
  • Chorioallantoic Membrane
  • Female
  • HEK293 Cells
  • Humans
  • Lung Neoplasms/drug therapy/*genetics/pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Myeloid Cells/*pathology
  • Pleural Cavity/cytology/pathology
  • Pleural Effusion, Malignant/drug therapy/*genetics/pathology
  • Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors/*genetics/metabolism
  • RNA, Small Interfering/metabolism
  • Spleen/cytology/pathology
  • Up-Regulation
  • Xenograft Model Antitumor Assays
Publication details
DOI: 10.1038/ncomms15205
Journal: Nat Commun
Pages: 15205 
Work Type: Original
Location: CPC-M
Disease Area: LC
Partner / Member: HMGU
Access-Number: 28508873
See publication on PubMed

DZL Engagements