Loss of REDD1 "Reprograms" Lipid Metabolism to Drive Progression of RAS-Mutant Tumors
Key findings
- RAS-mutant cells "reprogram" certain metabolic processes to adapt to the metabolic stress induced by RAS mutations; thus, the body's own stress response pathways might be able to prevent RAS-mediated tumor progression
- In this study, loss of the stress response gene REDD1 in RAS-mutant cells converted preneoplastic lesions into aggressive and metastatic tumors
- Biochemical and metabolic experiments showed that loss of REDD1 activated lipid uptake and fatty acid oxidation to meet the metabolic and energetic demands of RAS activation
- In vivo studies demonstrated the vulnerability of these tumors to antioxidant depletion, and analysis of human lung and pancreas carcinomas showed that decreased REDD1 expression predicted poor patient survival exclusively in RAS-mutant tumors
- RAS-mutant lung and pancreas cancers with low REDD1 levels have distinct and potentially therapeutically actionable vulnerabilities
Activating mutations in the RAS family of genes drive many aggressive human cancers, but selective targeting of downstream pathways has met with limited success. One major reason is that the mutant cells "reprogram" certain metabolic processes to adapt to the metabolic stress induced by RAS mutations.
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Thus, endogenous stress response pathways might be able to prevent RAS-mediated tumor progression. With this in mind, Leif W. Ellisen, MD, PhD, and Nabeel Bardeesy, PhD, of the Massachusetts General Hospital Cancer Center, and colleagues studied REDD1, which is upregulated in response to hypoxia and energy stress and helps regulate a number of pathologic cellular stress responses.
In Genes & Development, the team reports that REDD1 loss is a hallmark and driver of a previously unidentified RAS-mutant tumor subset characterized by reprogramming of lipid metabolism, rapid progression and poor outcomes.
Key Findings
- In genetically engineered mouse models, RAS mutation alone in lung and pancreatic epithelium induced preneoplastic lesions, whereas loss of REDD1 in RAS-mutant cells promoted fast-growing invasive carcinomas and distant metastasis
- In human RAS-mutant cells, REDD1 deficiency led to increased lipid uptake and storage and suppression of new lipogenesis
- Loss of REDD1 in RAS-mutant human cells increased fatty acid oxidation (which these cells rely on for energy and detoxification of reactive oxygen species) and increased levels of the key antioxidant glutathione
- In mouse models of lung cancer, increased fatty acid oxidation led to aggressive tumor progression; treatment of the mice with buthionine sulfoximine, a glutathione synthesis inhibitor, consistently arrested tumor progression
- REDD1-deficient, RAS-mutant cells co-opted hypoxia-inducible factor 1 and the peroxisome proliferator–activated receptor γ while activating CD36 (a prometastatic factor in multiple different cancers) to promote lipid uptake, altered metabolism and enhanced cell migration
- Data from the Cancer Genome Atlas showed survival of patients with RAS-mutant lung and pancreatic carcinomas expressing the lowest levels of REDD1 was approximately one-third that of patients whose tumors expressed the highest levels (P=0.015); remarkably, there was no such link between survival and REDD1 in RAS wild-type tumors
Therapeutic Implications
Combination therapies targeting the metabolic alterations described in this study, such as increased glutathione, are likely to be effective against REDD1-deficient, RAS-mutant tumors. For example, while clinical trials of buthionine sulfoximine have not yielded responses in a large proportion of tumors, targeting REDD1-deficient, RAS-mutant cancers may be more successful.
CD36 is also a potential therapeutic target, as CD36 inhibition has proven relatively nontoxic in preclinical studies.
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