Mutant KRAS promotes malignant pleural effusion formation

Nature Communications
Theodora AgaliotiGeorgios T Stathopoulos

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.

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Citations

Jan 30, 2018·Cellular & Molecular Immunology·Teizo Yoshimura
Dec 13, 2017·Cold Spring Harbor Perspectives in Medicine·Jane CullisDafna Bar-Sagi
Oct 1, 2019·Diseases of the Colon and Rectum·Yuji MiyamotoHideo Baba
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Feb 11, 2019·Journal of Natural Medicines·Cheolsun HanMinoru Narita
Aug 25, 2019·Medicina·Kristijan SkokAnton Crnjac
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Mar 29, 2018·Cancer Research·Malamati VrekaGeorgios T Stathopoulos
Jan 27, 2021·Cancers·Magda Spella, Georgios T Stathopoulos
Oct 31, 2020·Biochemical Society Transactions·Swati Singh, Matthew J Smith
Apr 23, 2021·Advanced Therapeutics·Deniz A BölükbasSilke Meiners
Jul 16, 2021·Journal of Radiation Research·Lue SunYuki Sugiura
Jul 22, 2021·Scientific Reports·Konstantina Pefani-AntimisiariSophia G Antimisiaris
Aug 15, 2021·Science Advances·Lilan ZhaoNicola Gagliani
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Aug 9, 2021·International Journal of Radiation Oncology, Biology, Physics·Verdiana TrappettiValentin Djonov
Oct 26, 2021·Current Opinion in Oncology·Yunchang LiChuan Xu

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Datasets Mentioned

BETA
GSE58190
GSE85021

Methods Mentioned

BETA
biopsies
flow cytometry
ELISA
PCR
lavage
flow
fluorescence-activated cell sorting
FACS
Assay
transgenic

Software Mentioned

Prism
BioEdit
FloMax
MatLab
Excel
Living Image
Fiji
GraphPad
Affymetrix Expression Console

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