University of Texas Southwestern Medical Center, Department of Dermatology, Dallas, Texas.
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas.
Cancer Res. 2022 Apr 1;82(7):1251-1266. doi: 10.1158/0008-5472.CAN-21-2062.
Despite being the leading cause of cancer deaths, metastasis remains a poorly understood process. To identify novel regulators of metastasis in melanoma, we performed a large-scale RNA sequencing screen of 48 samples from patient-derived xenograft (PDX) subcutaneous melanomas and their associated metastases. In comparison with primary tumors, expression of glycolytic genes was frequently decreased in metastases, whereas expression of some tricarboxylic acid (TCA) cycle genes was increased in metastases. Consistent with these transcriptional changes, melanoma metastases underwent a metabolic switch characterized by decreased levels of glycolytic metabolites and increased abundance of TCA cycle metabolites. A short isoform of glyceraldehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS) lacking the N-terminal domain suppressed metastasis and regulated this metabolic switch. GAPDHS was downregulated in metastatic nodules from PDX models as well as in human patients. Overexpression of GAPDHS was sufficient to block melanoma metastasis, whereas its inhibition promoted metastasis, decreased glycolysis, and increased levels of certain TCA cycle metabolites and their derivatives including citrate, fumarate, malate, and aspartate. Isotope tracing studies indicated that GAPDHS mediates this shift through changes in pyruvate carboxylase activity and aspartate synthesis, both metabolic pathways critical for cancer survival and metastasis. Together, these data identify a short isoform of GAPDHS that limits melanoma metastasis and regulates central carbon metabolism.
This study characterizes metabolic changes during cancer metastasis and identifies GAPDHS as a novel regulator of these processes in melanoma cells.
尽管转移是癌症死亡的主要原因，但它仍然是一个了解甚少的过程。为了确定黑色素瘤转移的新调节因子，我们对来自患者来源的异种移植物（PDX）皮下黑色素瘤及其相关转移的 48 个样本进行了大规模的 RNA 测序筛选。与原发性肿瘤相比，转移中糖酵解基因的表达经常降低，而一些三羧酸（TCA）循环基因的表达在转移中增加。与这些转录变化一致，黑色素瘤转移经历了代谢转换，其特征是糖酵解代谢物水平降低，TCA 循环代谢物丰度增加。甘油醛-3-磷酸脱氢酶（GAPDHS）的短同工型，缺少 N 端结构域的精子发生（GAPDHS），抑制转移并调节这种代谢转换。GAPDHS 在 PDX 模型和人类患者的转移性结节中下调。GAPDHS 的过表达足以阻止黑色素瘤转移，而其抑制促进转移，降低糖酵解，并增加某些 TCA 循环代谢物及其衍生物的水平，包括柠檬酸、富马酸、苹果酸和天冬氨酸。同位素追踪研究表明，GAPDHS 通过改变丙酮酸羧化酶活性和天冬氨酸合成来介导这种转变，这两种代谢途径对癌症的存活和转移都至关重要。总之，这些数据确定了 GAPDHS 的短同工型，它限制了黑色素瘤的转移并调节了中央碳代谢。
本研究描述了癌症转移过程中的代谢变化，并确定 GAPDHS 是黑色素瘤细胞中这些过程的新调节因子。
