In vivo library screening identifies the metabolic enzyme aldolase A as a promoter of metastatic lung colonization

• DOI: 10.1016/j.isci.2021.102425
• Publication Date: 2021-04-21T04:14:01Z
• Authors: Zhenbo Tu; Shengqi Hou; Yurong Zheng; Maerjianghan Abuduli; Tamer Onder; Andrew M. Intlekofer; Antoine E. Karnoub
• Keywords: 0303 health sciences; Cancer systems biology; Science; Q; Article; 3. Good health; 03 medical and health sciences; Cancer; Cancer systems biology; Metabolomics; Metabolomics; Science and technology; Cancer Systems Biology; Cancer

Elucidations of the factors that promote the growth of disseminated tumor cells (DTCs) into life-threatening lesions stand to provide much needed prognostic and therapeutic targets of translational utility for patients with metastatic cancer. To identify such regulators, we conducted gain-of-function cDNA library screening to discover genes that foster prostate cancer cell colonization of mouse lungs as an experimental model. Our efforts identified the metabolic enzyme aldolase A (ALDOA) as a driver of cancer cell motility, anchorage-independent growth, and metastatic colonization, and as a prognosticator of adverse patient outcome across many malignancies, including prostate, breast, pancreatic, and liver cancers. Metabolomics coupled with biochemical and functional analyses revealed that ALDOA triggered the activation of adenosine-5'-monophosphate (AMP)-activated protein kinase (AMPK), which we demonstrate played essential promalignant activities in ALDOA-expressing cells. Collectively, these findings unveiled vivo approaches to identify metastatic colonization regulators and uncovered previously undescribed roles for ALDOA-AMPK pathway in tumor progression.