PO.TB07.01 · 肿瘤生物学
通过表型和代谢适应对乳腺癌转移的氧化还原调控
Redox regulation of breast cancer metastasis via phenotypic and metabolic adaptation
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摘要 Abstract
中文摘要
背景:肿瘤异质性通过选择具有上皮-间充质(EMT)可塑性和干性的亚群来推动乳腺癌转移。在PyMT小鼠模型中,抗氧化酶谷胱甘肽过氧化物酶2(GPx2)的缺失通过△Np63调控的杂合EMT和脂肪酸氧化(FAO)驱动的代谢促进表型和代谢重编程。
结果:利用我们新构建的PyMT/GPx2敲除(KO)转基因小鼠模型,我们观察到与对照肿瘤相比,活性氧(ROS)、HIF1alpha稳定化、血管畸形、增殖(Ki67)、干性(类器官形成)和肺转移显著增加。GPx2缺陷肿瘤显著富集共表达p63、KRT8和KRT14的杂合EMT细胞。流式细胞术证实,约85%的GPx2-KO肿瘤细胞为杂合型(CD104+/CD44+),仅有少量上皮型(CD104+/CD44-,约4%)和间充质型(CD104-/CD44+,约0.8%)组分。代谢分析显示FAO是GPx2-KO肿瘤的主要能量来源,Seahorse实验显示线粒体ATP产生升高、OCR/ECAR比值升高以及棕榈酸氧化增强,均支持这一点。GPx2缺失增加了p-AMPK,提示AMPK介导的OXPHOS激活,并上调GLUT1,同时抑制从头脂肪生成。这些变化表明肿瘤依赖于通过CD36/CPT1介导的beta-氧化摄取外源性脂肪酸。值得注意的是,来源于GPx2-KO肿瘤的肺转移灶表现出向糖酵解代谢的转变,凸显了播散过程中的代谢可塑性。
结论:GPx2缺失将氧化还原失调与EMT和代谢重编程整合在一起,促进了具有高转移潜能和适应性能量代谢的杂合E/M细胞的形成。
临床意义:靶向△Np63信号或FAO通路可能选择性地清除代谢灵活、具侵袭性的杂合肿瘤群体,为减轻乳腺癌转移提供潜在策略。
查看英文原文 English abstract
Background: Tumor heterogeneity fuels breast cancer metastasis by selecting subpopulations withepithelial-mesenchymal (EMT) plasticity and stemness. Loss of the antioxidant enzyme glutathione peroxidase 2 (GPx2) in the PyMT mouse model promotes phenotypic and metabolic reprogramming through ΔNp63-regulated hybrid EMT and fatty acidoxidation (FAO)-driven metabolism.
Results: Using our newly engineered PyMT/GPx2 knockout (KO) transgenic mouse model, we observed a striking increase in reactive oxygen species (ROS), HIF1alpha stabilization, vascular malformation, proliferation (Ki67), stemness (organoid formation), and lung metastasis compared with control tumors. GPx2-deficient tumors were markedly enrichedfor hybrid EMT cells co-expressing p63, KRT8, and KRT14. Flow cytometry confirmed that ~85% of GPx2-KO tumor cells were hybrid (CD104⁺/CD44⁺), with only minor epithelial (CD104⁺/CD44⁻, ~4%) and mesenchymal (CD104⁻/CD44⁺, ~0.8%) fractions. Metabolic profiling revealed FAO as the dominant energy source in GPx2-KO tumors, supported by Seahorse assays showing elevated mitochondrial ATP production, a higherOCR/ECAR ratio, and enhanced palmitate oxidation. GPx2 loss increased p-AMPK,indicative of AMPK-mediated OXPHOS activation, and upregulated GLUT1 whilesuppressing de novo lipogenesis. These changes indicate dependence on exogenousfatty acids through CD36/CPT1-mediated beta-oxidation. Notably, lung metastases derivedfrom GPx2-KO tumors showed a shift toward glycolytic metabolism, highlightingmetabolic plasticity during dissemination.
Conclusion: GPx2 loss integrates redox dysregulation with EMT and metabolic reprogramming, fostering hybrid E/M cells endowed with high metastatic potential and adaptive energymetabolism.
Clinical implications: Targeting ΔNp63 signaling or FAO pathways may selectively eliminate metabolically flexible, aggressive hybrid tumor populations, offering a potential strategy to mitigate breast cancer metastasis.
利益披露 Disclosure
R. Hazan, None..
P. chaudhary, None..
M. kaur, None..
I. M. , Bethesda, None.