Mutant KRAS promotes malignant pleural effusion formation

Theodora Agalioti; Anastasios D Giannou; Anthi C Krontira; Nikolaos I Kanellakis; Danai Kati; Malamati Vreka; Mario Pepe; Magda Spella; Ioannis Lilis; Dimitra E Zazara; Eirini Nikolouli; Nikolitsa Spiropoulou; Andreas Papadakis; Konstantina Papadia; Apostolos Voulgaridis; Vaggelis Harokopos; Panagiota Stamou; Silke Meiners; Oliver Eickelberg; Linda A Snyder; Sophia G Antimisiaris; Dimitrios Kardamakis; Ioannis Psallidas; Antonia Marazioti; Georgios T Stathopoulos

doi:10.1038/ncomms15205

Mutant KRAS promotes malignant pleural effusion formation

Nat Commun. 2017 May 16:8:15205. doi: 10.1038/ncomms15205.

Authors

Theodora Agalioti¹, Anastasios D Giannou¹, Anthi C Krontira¹, Nikolaos I Kanellakis^{1

2}, Danai Kati¹, Malamati Vreka^{1

3}, Mario Pepe³, Magda Spella¹, Ioannis Lilis¹, Dimitra E Zazara¹, Eirini Nikolouli¹, Nikolitsa Spiropoulou¹, Andreas Papadakis¹, Konstantina Papadia⁴, Apostolos Voulgaridis⁵, Vaggelis Harokopos⁶, Panagiota Stamou⁷, Silke Meiners³, Oliver Eickelberg³, Linda A Snyder⁸, Sophia G Antimisiaris⁴, Dimitrios Kardamakis⁹, Ioannis Psallidas^{1

2}, Antonia Marazioti¹, Georgios T Stathopoulos^{1

3}

Affiliations

¹ Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece.
² Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHS Trust, Churchill Hospital Old Road, Oxford OX3 7LE, UK.
³ Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilians University and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), 81377 Munich, Germany.
⁴ Laboratory for Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, University of Patras, and Foundation for Research and Technology Hellas, Institute of Chemical Engineering, FORTH/ICE-HT, 26504 Rio, Greece.
⁵ Department of Pulmonary Medicine, Rio University Hospital, Faculty of Medicine, University of Patras, 26504 Rio, Greece.
⁶ Genomics Facility, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Attica 16672, Greece.
⁷ Department of Hematology, Faculty of Medicine, University of Patras, Rio, Achaia 26504, Greece.
⁸ Oncology Discovery Research, Janssen R&D LLC, Spring House, Pennsylvania, 19477 USA.
⁹ Department of Radiation Oncology and Stereotactic Radiotherapy, Faculty of Medicine, University of Patras, 26504 Rio, Greece.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy
Adenocarcinoma / genetics*
Adenocarcinoma / pathology
Adenocarcinoma of Lung
Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Benzimidazoles / pharmacology
Benzimidazoles / therapeutic use
Cell Line, Tumor
Chemokine CCL2 / antagonists & inhibitors
Chemokine CCL2 / metabolism
Chickens
Chorioallantoic Membrane
Female
HEK293 Cells
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Myeloid Cells / pathology*
Pleural Cavity / cytology
Pleural Cavity / pathology
Pleural Effusion, Malignant / drug therapy
Pleural Effusion, Malignant / genetics*
Pleural Effusion, Malignant / pathology
Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
Proto-Oncogene Proteins p21(ras) / genetics*
Proto-Oncogene Proteins p21(ras) / metabolism
RNA, Small Interfering / metabolism
Spleen / cytology
Spleen / pathology
Up-Regulation
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Benzimidazoles
CCL2 protein, human
Ccl2 protein, mouse
Chemokine CCL2
KRAS protein, human
RNA, Small Interfering
deltarasin
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)