Tu Zhenbo, Hou Shengqi, Zheng Yurong, Abuduli Maerjianghan, Onder Tamer, Intlekofer Andrew M, Karnoub Antoine E
Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York 10065, USA.
iScience. 2021 Apr 20;24(5):102425. doi: 10.1016/j.isci.2021.102425. eCollection 2021 May 21.
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.
阐明促进播散肿瘤细胞（DTCs）生长为危及生命病变的因素，有望为转移性癌症患者提供急需的具有转化应用价值的预后和治疗靶点。为了识别此类调节因子，我们进行了功能获得性cDNA文库筛选，以发现促进前列腺癌细胞在小鼠肺中定植的基因，作为实验模型。我们的研究确定代谢酶醛缩酶A（ALDOA）是癌细胞运动、不依赖贴壁生长和转移定植的驱动因子，也是包括前列腺癌、乳腺癌、胰腺癌和肝癌在内的许多恶性肿瘤患者不良预后的预测指标。代谢组学结合生化和功能分析表明，ALDOA触发了5'-单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）的激活，我们证明AMPK在表达ALDOA的细胞中发挥了重要的促癌活性。总的来说，这些发现揭示了识别转移定植调节因子的体内方法，并揭示了ALDOA-AMPK途径在肿瘤进展中以前未描述的作用。
