Tumours can be viewed as aberrant tissues or organs sustained by tumorigenic stem-like cells that engage into dysregulated histo/organogenetic processes. Paragangliomas, prototypical organoid tumours constituted by dysmorphic variants of the vascular and neural tissues found in normal paraganglia, provide a model to test this hypothesis. To understand the origin of paragangliomas, we built a biobank comprising 77 cases, 18 primary cultures, 4 derived cell lines, 80 patient-derived xenografts and 11 cell-derived xenografts. We comparatively investigated these unique complementary materials using morphofunctional, ultrastructural and flow cytometric assays accompanied by microRNA studies. We found that paragangliomas contain stem-like cells with hybrid mesenchymal/vasculoneural phenotype, stabilized and expanded in the derived cultures. The viability and growth of such cultures depended on the downregulation of the miR-200 and miR-34 families, which allowed high PDGFRA and ZEB1 protein expression levels. Both tumour tissue- and cell culture-derived xenografts recapitulated the vasculoneural paraganglioma structure and arose from mesenchymal-like cells through a fixed developmental sequence. First, vasculoangiogenesis organized the microenvironment, building a perivascular niche which in turn supported neurogenesis. Neuroepithelial differentiation was associated with severe mitochondrial dysfunction, not present in cultured paraganglioma cells, but acquired in vivo during xenograft formation. Vasculogenesis was the Achilles’ heel of xenograft development. In fact, imatinib, that targets endothelial-mural signalling, blocked paraganglioma xenograft formation (11 xenografts from 12 cell transplants in the control group versus 2 out of 10 in the treated group, P = 0.0015). Overall our key results were unaffected by the SDHx gene carrier status of the patient, characterized for 70 out of 77 cases. In conclusion, we explain the biphasic vasculoneural structure of paragangliomas and identify an early and pharmacologically actionable phase of paraganglioma organization.

肿瘤可以看作是由致瘤的干细胞样细胞维持的异常组织或器官，这些干细胞参与了异常的组织/器官发生过程。副神经节瘤是典型的神经节样瘤，由正常副神经节中发现的血管和神经组织畸形变体构成，为检验这一假设提供了模型。为了了解副神经节瘤的起源，我们建立了一个生物库，其中包括77例病例，18种原代培养物，4种衍生细胞系，80种患者来源的异种移植物和11种细胞来源的异种移植物。我们通过形态功能，超微结构和流式细胞仪分析与microRNA研究相比较，研究了这些独特的补充材料。我们发现副神经节瘤包含具有间充质/血管神经表型的干细胞样细胞，在衍生培养物中稳定并扩展。这种培养物的生存能力和生长取决于miR-200和miR-34家族的下调，这使得PDGFRA和ZEB1蛋白表达水平较高。肿瘤组织和细胞培养衍生的异种移植物都概括了血管神经旁神经节瘤的结构，并通过固定的发育序列从间充质样细胞中产生。首先，血管新生组织了微环境，建立了血管周围的生态位，进而支持了神经发生。神经上皮分化与严重的线粒体功能障碍有关，并不存在于培养的副神经节瘤细胞中，而是在异种移植形成过程中在体内获得的。血管生成是异种移植发展的致命弱点。实际上，靶向血管内皮细胞信号传导的伊马替尼，P  = 0.0015）。总体而言，我们的关键结果不受患者SDHx基因携带者状况的影响，在77例病例中，有70例具有特征性。总之，我们解释了副神经节瘤的双相血管神经结构，并确定了副神经节瘤组织的早期和药理作用阶段。