Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany.
Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany.
Endocr Relat Cancer. 2020 Nov;27(11):625-640. doi: 10.1530/ERC-20-0205.
Mutations that drive the stabilization of hypoxia inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are known to predispose to the development of pheochromocytomas and paragangliomas (PPGLs). However, any role of HIF2α in predisposition to metastatic disease remains unclear. To assess such a role we combined gene-manipulations in pheochromocytoma cell lines with retrospective analyses of patient data and gene expression profiling in tumor specimens. Among 425 patients with PPGLs identified with mutations in tumor-susceptibility genes, those with tumors due to activation of pseudohypoxic pathways had a higher frequency of metastatic disease than those with tumors due to activation of kinase-signaling pathways, even without inclusion of patients with mutations in SDHB (18.6% vs 4.3% in, P < 0.0001). Three out of nine (33%) patients with gain-of-function mutations in HIF2α had metastatic disease. In cell line studies, elevated expression of HIF2α enhanced cell proliferation and led to increased migration and invasion capacity. Moreover, HIF2α expression in HIF2α-deficient cells resulted in increased cell motility, diffuse cluster formation and emergence of pseudopodia indicating changes in cell adhesion and cytoskeletal remodeling. In a mouse liver metastasis model, Hif2a enhanced the metastatic load. Transcriptomics data revealed alterations in focal adhesion and extracellular matrix-receptor interactions in HIF2α-mutated PPGLs. Our translational findings demonstrate that HIF2α supports pro-metastatic behavior in PPGLs, though other factors remain critical for subsequent transition to metastasis. We identified LAMB1 and COL4A2 as new potential therapeutic targets for HIF2α-driven PPGLs. Identified HIF2α downstream targets might open a new therapeutic window for aggressive HIF2α-expressing tumors.
已知驱动缺氧诱导因子 2α（HIF2α）及其下游假缺氧信号稳定的突变会导致嗜铬细胞瘤和副神经节瘤（PPGL）的发生。然而，HIF2α 在易患转移性疾病中的任何作用仍不清楚。为了评估这种作用，我们将嗜铬细胞瘤细胞系中的基因操作与患者数据的回顾性分析和肿瘤标本中的基因表达谱分析相结合。在 425 名患有 PPGL 且肿瘤易感性基因发生突变的患者中，由于假缺氧途径激活而导致肿瘤的患者比由于激酶信号途径激活而导致肿瘤的患者发生转移性疾病的频率更高，即使不包括 SDHB 突变的患者也是如此（18.6%对 4.3%，P<0.0001）。在 9 名 HIF2α 获得性功能突变患者中，有 3 名（33%）发生转移性疾病。在细胞系研究中，HIF2α 的高表达增强了细胞增殖，并导致迁移和侵袭能力增加。此外，在 HIF2α 缺陷细胞中表达 HIF2α 导致细胞迁移率增加、弥散性集落形成和伪足的出现，表明细胞黏附和细胞骨架重塑发生变化。在小鼠肝转移模型中，Hif2a 增强了转移负荷。转录组学数据显示，HIF2α 突变的 PPGL 中黏附和细胞外基质-受体相互作用发生改变。我们的转化研究结果表明，HIF2α 支持 PPGL 的促转移行为，尽管其他因素对于随后向转移的转变仍然至关重要。我们确定 LAMB1 和 COL4A2 为 HIF2α 驱动的 PPGL 的新的潜在治疗靶点。确定的 HIF2α 下游靶点可能为表达 HIF2α 的侵袭性肿瘤开辟新的治疗窗口。
