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REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors
Shuxi Qiao1,2, Siang-Boon Koh1,2, Varunika Vivekanandan1
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
Abstract:
Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion in genetically engineered mouse models (GEMMs) of KRAS-dependent pancreatic and lung adenocarcinomas converts preneoplastic lesions into invasive and metastatic carcinomas. Metabolic profiling reveals that REDD1-deficient/RAS mutant cells exhibit enhanced uptake of lysophospholipids and lipid storage, coupled to augmented fatty acid oxidation that sustains both ATP levels and ROS-detoxifying NADPH. Mechanistically, REDD1 loss triggers HIF-dependent activation of a lipid storage pathway involving PPARγ and the prometastatic factor CD36. Correspondingly, decreased REDD1 expression and a signature of REDD1 loss predict poor outcomes selectively in RAS mutant but not RAS wild-type human lung and pancreas carcinomas. Collectively, our findings reveal the REDD1-mediated stress response as a novel tumor suppressor whose loss defines a RAS mutant tumor subset characterized by reprogramming of lipid metabolism, invasive and metastatic progression, and poor prognosis. This work thus provides new mechanistic and clinically relevant insights into the phenotypic heterogeneity and metabolic rewiring that underlies these common cancers.
Insights
Loss of REDD1 reprograms lipid metabolism in RAS-mutant cancers, driving aggressive tumor growth and metastasis. This metabolic shift explains poor outcomes in these aggressive cancers.
Area of Science:
- Oncology
- Metabolic Regulation
- Cancer Biology
Background:
- Activating RAS mutations drive aggressive, treatment-refractory human cancers.
- RAS activation induces metabolic stress, limiting tumor formation.
- REDD1 (regulated in development and DNA damage response 1) is a key stress-induced metabolic regulator.
Purpose of the Study:
- To investigate the role of REDD1 loss in the progression of RAS-mutant cancers.
- To elucidate the metabolic reprogramming driven by REDD1 loss in RAS-mutant tumors.
- To determine the clinical relevance of REDD1 expression in human cancers.
Main Methods:
- Utilized genetically engineered mouse models (GEMMs) of KRAS-dependent pancreatic and lung adenocarcinomas with REDD1 deletion.
- Performed metabolic profiling to analyze lipid metabolism in REDD1-deficient/RAS-mutant cells.
- Assessed the expression of REDD1 and related markers in human lung and pancreas carcinomas.
Main Results:
- REDD1 deletion in KRAS-driven cancers promoted conversion of preneoplastic lesions to invasive, metastatic carcinomas.
- REDD1-deficient/RAS-mutant cells showed enhanced lysophospholipid uptake, lipid storage, and fatty acid oxidation.
- Mechanistically, REDD1 loss activated a HIF-dependent, PPARγ/CD36-mediated lipid storage pathway.
- Decreased REDD1 expression correlated with poor prognosis specifically in RAS-mutant lung and pancreas cancers.
Conclusions:
- REDD1 acts as a tumor suppressor in RAS-mutant cancers.
- Loss of REDD1 triggers metabolic reprogramming, favoring lipid metabolism and tumor progression.
- REDD1 loss defines a subset of RAS-mutant cancers with invasive/metastatic potential and poor prognosis.
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