PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia.

Saliakoura, Maria; Rossi, Sebastiano Matteo; Pozzato, Chiara; Heidel, Florian H.; Schnöder, Tina M.; Savic Prince, Spasenija; Bubendorf, Lukas; Pinton, Paolo; Schmid, Ralph A.; Baumgartner, Johanna; Freigang, Stefan; Berezowska, Sabina A.; Rimessi, Alessandro; Konstantinidou, Georgia (2020). PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia. Nature cell biology, 22(11), pp. 1382-1395. Springer Nature 10.1038/s41556-020-00592-8

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Mutant KRAS modulates the metabolic plasticity of cancer cells to confer a growth advantage during hypoxia, but the molecular underpinnings are largely unknown. Using a lipidomic screen, we found that PLCγ1 is suppressed during hypoxia in KRAS-mutant human lung adenocarcinoma cancer cell lines. Suppression of PLCγ1 in hypoxia promotes a less oxidative cancer cell metabolism state, reduces the formation of mitochondrial reactive oxygen species and switches tumour bioenergetics towards glycolysis by impairing Ca2+ entry into the mitochondria. This event prevents lipid peroxidation, antagonizes apoptosis and increases cancer cell proliferation. Accordingly, loss of function of Plcg1 in a mouse model of KrasG12D-driven lung adenocarcinoma increased the expression of glycolytic genes, boosted tumour growth and reduced survival. In patients with KRAS-mutant lung adenocarcinomas, low PLCγ1 expression correlates with increased expression of hypoxia markers and predicts poor patient survival. Thus, our work reveals a mechanism of cancer cell adaptation to hypoxia with potential therapeutic value.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology

UniBE Contributor:

Saliakoura, Maria; Rossi, Sebastiano Matteo; Pozzato, Chiara; Schmid, Ralph; Baumgartner, Johanna Maria Magdalena; Freigang, Stefan Bernd; Berezowska, Sabina Anna and Konstantinidou, Georgia

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1476-4679

Publisher:

Springer Nature

Language:

English

Submitter:

Celine Joray

Date Deposited:

23 Nov 2020 14:51

Last Modified:

29 Nov 2020 02:45

Publisher DOI:

10.1038/s41556-020-00592-8

PubMed ID:

33077911

BORIS DOI:

10.7892/boris.148242

URI:

https://boris.unibe.ch/id/eprint/148242

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