Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
Cancer Res. 2020 Jul 1;80(13):2751-2763. doi: 10.1158/0008-5472.CAN-19-2884. Epub 2020 May 11.
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by multiorgan hamartomas, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). TSC2 deficiency leads to hyperactivation of mTOR Complex 1 (mTORC1), a master regulator of cell growth and metabolism. Phospholipid metabolism is dysregulated upon TSC2 loss, causing enhanced production of lysophosphatidylcholine (LPC) species by TSC2-deficient tumor cells. LPC is the major substrate of the secreted lysophospholipase D autotaxin (ATX), which generates two bioactive lipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). We report here that ATX expression is upregulated in human renal angiomyolipoma-derived TSC2-deficient cells compared with TSC2 add-back cells. Inhibition of ATX via the clinically developed compound GLPG1690 suppressed TSC2-loss associated oncogenicity and and induced apoptosis in TSC2-deficient cells. GLPG1690 suppressed AKT and ERK1/2 signaling and profoundly impacted the transcriptome of these cells while inducing minor gene expression changes in TSC2 add-back cells. RNA-sequencing studies revealed transcriptomic signatures of LPA and S1P, suggesting an LPA/S1P-mediated reprogramming of the TSC lipidome. In addition, supplementation of LPA or S1P rescued proliferation and viability, neutral lipid content, and AKT or ERK1/2 signaling in human TSC2-deficient cells treated with GLPG1690. Importantly, TSC-associated renal angiomyolipomas have higher expression of LPA receptor 1 and S1P receptor 3 compared with normal kidney. These studies increase our understanding of TSC2-deficient cell metabolism, leading to novel potential therapeutic opportunities for TSC and LAM. SIGNIFICANCE: This study identifies activation of the ATX-LPA/S1P pathway as a novel mode of metabolic dysregulation upon TSC2 loss, highlighting critical roles for ATX in TSC2-deficient cell fitness and in TSC tumorigenesis.
结节性硬化症复合征（TSC）是一种常染色体显性疾病，其特征为多器官错构瘤，包括肾血管平滑肌脂肪瘤和肺淋巴管平滑肌瘤病（LAM）。TSC2 缺陷导致 mTOR 复合物 1（mTORC1）的过度激活，mTORC1 是细胞生长和代谢的主要调节因子。磷脂代谢在 TSC2 缺失时失调，导致 TSC2 缺陷肿瘤细胞中溶血磷脂酰胆碱（LPC）的产量增加。LPC 是分泌型溶血磷脂酶 D 自分泌运动因子（ATX）的主要底物，ATX 产生两种生物活性脂质，溶血磷脂酸（LPA）和鞘氨醇-1-磷酸（S1P）。我们在此报告，与 TSC2 恢复细胞相比，人肾血管平滑肌脂肪瘤来源的 TSC2 缺陷细胞中 ATX 表达上调。通过临床开发的化合物 GLPG1690 抑制 ATX，可抑制 TSC2 缺失相关的致癌性，并诱导 TSC2 缺陷细胞凋亡。GLPG1690 抑制 AKT 和 ERK1/2 信号通路，并显著影响这些细胞的转录组，同时在 TSC2 恢复细胞中引起较小的基因表达变化。RNA 测序研究揭示了 LPA 和 S1P 的转录组特征，表明 LPA/S1P 介导了 TSC 脂质组的重编程。此外，在 GLPG1690 处理的人 TSC2 缺陷细胞中，补充 LPA 或 S1P 可挽救增殖和活力、中性脂质含量以及 AKT 或 ERK1/2 信号通路。重要的是，与正常肾脏相比，TSC 相关的肾血管平滑肌脂肪瘤中 LPA 受体 1 和 S1P 受体 3 的表达更高。这些研究增加了我们对 TSC2 缺陷细胞代谢的理解，为 TSC 和 LAM 提供了新的潜在治疗机会。意义：本研究确定了 ATX-LPA/S1P 通路的激活是 TSC2 缺失时代谢失调的一种新方式，突出了 ATX 在 TSC2 缺陷细胞适应性和 TSC 肿瘤发生中的关键作用。
