In vivo library screening identifies the metabolic enzyme aldolase A as a promoter of metastatic lung colonization
Zhenbo Tu,
Shengqi Hou,
Yurong Zheng,
Maerjianghan Abuduli,
Tamer Onder,
Andrew M. Intlekofer,
Antoine E. Karnoub
Affiliations
Zhenbo Tu
Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Shengqi Hou
Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York 10065, USA
Yurong Zheng
Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Maerjianghan Abuduli
Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Tamer Onder
Department of Molecular Biology and Genetics, School of Medicine, Koç University, Istanbul 34450, Turkey
Andrew M. Intlekofer
Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York 10065, USA
Antoine E. Karnoub
Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Corresponding author
Summary: 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.
