Succinyl-CoA ligase ADP-forming subunit beta promotes stress granule assembly to regulate redox and drive cancer metastasis.

Although recent studies demonstrate active mitochondrial metabolism in cancers, the precise mechanisms through which mitochondrial factors contribute to cancer metastasis remain elusive. Through a customized mitochondrion RNAi screen, we identified succinyl-CoA ligase ADP-forming subunit beta (SUCLA2) as a critical anoikis resistance and metastasis driver in human cancers. Mechanistically, SUCLA2, but not the alpha subunit of its enzyme complex, relocates from mitochondria to the cytosol upon cell detachment where SUCLA2 then binds to and promotes the formation of stress granules. SUCLA2-mediated stress granules facilitate the protein translation of antioxidant enzymes including catalase, which mitigates oxidative stress and renders cancer cells resistant to anoikis. We provide clinical evidence that SUCLA2 expression correlates with catalase levels as well as metastatic potential in lung and breast cancer patients. These findings not only implicate SUCLA2 as an anticancer target, but also provide insight into a unique, noncanonical function of SUCLA2 that cancer cells co-opt to metastasize.

Metabolic inhibitor screening identifies dihydrofolate reductase as an inducer of the tumor immune escape mediator CD24.

Immune checkpoint inhibitors have improved the clinical management of some cancer cases, yet patients still fail to respond to immunotherapy. Dysregulated metabolism is a common feature of many cancers, and metabolites are known to modulate functions in cancer cells. To identify potential metabolic pathways involved in anti-tumor immune response, we employed a metabolic inhibitor-based drug screen in human lung cancer cell lines and examined expression changes in a panel of immune regulator genes. Notably, pharmacologic inhibition of dihydrofolate reductase (DHFR) downregulated cancer cell expression of cluster of differentiation 24 (CD24), an anti-phagocytic surface protein. Genetic modulation of DHFR resulted in decrease of CD24 expression, whereas tetrahydrofolate, the product of DHFR, enhanced CD24 expression. DHFR inhibition and the consequent CD24 decrease enhanced T cell-mediated tumor cell killing, whereas replenishment of DHFR or CD24 partially mitigated the immune-mediated tumor cell killing that resulted from methotrexate treatment in cancer cells. Moreover, publicly available clinical data analyses further revealed the link between DHFR, CD24, and the antitumor immune response in lung cancer patients. Our study highlights a novel connection between folate metabolism and the anti-tumor immune response and partially interprets how DHFR inhibitors lead to clinical benefits when combined with cancer immunotherapy agents.

EGFR-phosphorylated GDH1 harmonizes with RSK2 to drive CREB activation and tumor metastasis in EGFR-activated lung cancer.

The cancer metastasis process involves dysregulated oncogenic kinase signaling, but how this orchestrates metabolic networks and signal cascades to promote metastasis is largely unclear. Here we report that inhibition of glutamate dehydrogenase 1 (GDH1) and ribosomal S6 kinase 2 (RSK2) synergistically attenuates cell invasion, anoikis resistance, and immune escape in lung cancer and more evidently in tumors harboring epidermal growth factor receptor (EGFR)-activating or EGFR inhibitor-resistant mutations. Mechanistically, GDH1 is activated by EGFR through phosphorylation at tyrosine 135 and, together with RSK2, enhances the cAMP response element-binding protein (CREB) activity via CaMKIV signaling, thereby promoting metastasis. Co-targeting RSK2 and GDH1 leads to enhanced intratumoral CD8 T cell infiltration. Moreover, GDH1, RSK2, and CREB phosphorylation positively correlate with EGFR mutation and activation in lung cancer patient tumors. Our findings reveal a crosstalk between kinase, metabolic, and transcription machinery in metastasis and offer an alternative combinatorial therapeutic strategy to target metastatic cancers with activated EGFRs that are often EGFR therapy resistant.