Abstract 1551: Succinyl-CoA synthetase Beta-A: A novel metastasis promoting factor in lung cancer

Abstract Changes in metabolism occur when cancer cells disseminate from primary sites and metastasize. Mitochondrial metabolism plays an essential role in various biological processes of cancer cells, but the underlying mechanism through which mitochondrial factors contribute to cancer metastasis remains largely elusive. Anoikis is a form of apoptosis induced by loss of cell adhesion, and metastatic tumor cells must be anoikis resistant to survive during circulation before forming metastatic foci in distant organs. We performed an unbiased RNAi screen using a customized mitochondrion shRNA library and identified succinyl-CoA synthetase beta-A (A-SCS, also called SUCLA2), which is known to catalyze the reversible conversion of succinyl-CoA and ADP to succinate and ATP in the TCA cycle as an essential factor that promotes the survival of disseminated cancer cells during metastasis. We demonstrate that A-SCS manages redox balance during tumor metastasis, and this metabolic contribution is independent of its role in the TCA cycle. Mechanistically, A-SCS relocates from the mitochondria to the cytosol and binds to stress granules, promoting stress granules to express the redox-scavenging enzyme catalase upon cell detachment. This mitigates oxidative stress and makes cancer cells survive through anoikis, eventually promoting metastasis. A clinical correlation study comparing primary and metastasized tumors collected from lung cancer patients demonstrated that A-SCS levels align with catalase expression as well as the metastatic progression of lung cancer. Our finding provides an academic basis for developing new treatment targets against metastasis, which strikes elevated mitochondrial metabolism during cancer cell dissemination. Citation Format: Jihoon Kang, Jung Seok Hwang, Austin C. Boese, Sydney Shuff, Jaehyun Kim, Kiyoung Eun, Sumin Kang. Succinyl-CoA synthetase Beta-A: A novel metastasis promoting factor in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1551.