PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia
Maria Saliakoura1, Matteo Rossi Sebastiano1, Chiara Pozzato1
1Institute of Pharmacology, University of Bern, Bern, Switzerland.
Abstract:
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.
Insights
Mutant KRAS lung cancer cells adapt to low oxygen by suppressing PLCγ1, promoting glycolysis and growth. This metabolic shift impairs mitochondrial function, preventing cell death and enhancing tumor progression.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Mutant KRAS drives cancer cell growth, particularly under hypoxic conditions.
- The metabolic adaptations enabling this advantage remain poorly understood.
- Hypoxia-induced changes in cancer cell metabolism are critical for tumor progression.
Purpose of the Study:
- To elucidate the molecular mechanisms by which KRAS-mutant cancer cells adapt to hypoxia.
- To identify key proteins and pathways involved in metabolic reprogramming during hypoxia.
- To investigate the role of Phospholipase C gamma 1 (PLCγ1) in this adaptive process.
Main Methods:
- Lipidomic screening of KRAS-mutant lung adenocarcinoma cell lines under hypoxia.
- Functional assays assessing cellular metabolism, mitochondrial function, and apoptosis.
- Genetic manipulation (loss-of-function) in a mouse model of Kras-driven lung adenocarcinoma.
- Correlation analysis of PLCγ1 expression with hypoxia markers and survival in patient cohorts.
Main Results:
- PLCγ1 is suppressed in KRAS-mutant lung cancer cells during hypoxia.
- PLCγ1 suppression shifts metabolism towards glycolysis, reduces mitochondrial reactive oxygen species, and impairs mitochondrial calcium entry.
- Loss of PLCγ1 function enhances tumor growth, glycolysis, and reduces survival in a Kras-driven mouse model.
- Low PLCγ1 expression in patients correlates with hypoxia markers and predicts poor survival.
Conclusions:
- Suppression of PLCγ1 is a key mechanism for KRAS-mutant lung cancer adaptation to hypoxia.
- This adaptation involves metabolic reprogramming towards glycolysis, promoting proliferation and survival.
- PLCγ1 represents a potential therapeutic target for KRAS-mutant lung adenocarcinoma under hypoxic conditions.
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