基于甲状腺癌超声分子显像的肿瘤微循环介导的线粒体重塑调控机制

On the basis of clinical characteristics of high morbidity, low mortality.in thyroid carcinoma, identifying pathogenesis and proper evaluating the aggressivity of tumor has become a new problem that urgently need resolving. In present, contrast enhanced ultrasound (CEUS) provides imaging information for microcirculation and hypoxia microenvironment of thyroid carcinoma. Mitochondria are sensitive to oxygen tension, and their self-adjustment plays an important role in tumor regulation. Therefore, according to the characteristics of CEUS in thyroid carcinoma, this project will focus on mitochondrial remodeling, firstly, summarize the intrinsic link between ultrasonic imaging and tumor microcirculation in thyroid by the retrospective study, and to explore the clinical relevance between the vasculogenic mimicry and invasive nature of thyroid carcinoma. Moreover, we will investigate the changes of mitochondrial remodeling in thyroid cancer and cellular model with different pathological types. And then we will clarify the network between the development of thyroid carcinoma and mitochondrial remodeling. through cancer pathway phosphorylation microarrays. Lastly, we will elucidate the molecular processes of mitochondrial dynamics on invasiveness of thyroid carcinoma cells through molecular biological methods. This project aims to estimate the tumorigenesis and aggressivity of thyroid cancer and reveal its underlying mechanism, which is helpful to assess risk and prognosis, and lay the theoretical foundation for therapeutic targets applied in clinical translational medicine.

针对甲状腺癌高发病率、低死亡率的疾病特征，明确其发生机制及正确评估侵袭性是优化甲状腺癌临床治疗决策的关键问题。现有超声造影研究为甲状腺癌微循环及其介导的缺氧微环境提供了影像学依据，而线粒体作为氧张力敏感的细胞器，其自身调节在肿瘤调控中发挥重要作用。据此本项目基于甲状腺癌超声造影特征，以线粒体重塑为切入点，①通过大样本回顾性研究总结临床超声影像学与甲状腺微循环的内在联系，探讨血管生长拟态与甲状腺癌侵袭性的临床相关性；②结合组织标本与细胞模型，探讨不同病理类型的甲状腺癌线粒体失稳态的变化特征；通过信号通路磷酸化抗体芯片筛选，明确甲状腺癌发生发展与线粒体重塑之间的网络信号调节；③通过特异性分子生物学干预，阐明线粒体动力学异常对甲状腺癌微循环及侵袭转移调控的分子机制。本项目是对甲状腺癌的发生及其侵袭性预测评估的深入研究，有助于提示风险，判断预后，并为线粒体治疗靶点应用于临床转化医学奠定理论基础。

针对甲状腺癌高发病率、低死亡率的疾病特征，明确其发生机制及正确评估侵袭性是优化甲状腺癌临床治疗决策的关键问题。我们前期开展超声造影相关研究为甲状腺癌微循环及其介导的缺氧微环境提供了影像学依据，而线粒体作为氧张力敏感的细胞器，其自身调节在肿瘤调控中发挥重要作用。据此本项目基于甲状腺癌超声造影特征，以线粒体重塑为切入点：①回顾性分析我院甲状腺超声造影后经手术病理诊断为甲状腺癌且符合相应入组条件的患者，发现超声造影不均匀等高增强模式与甲状腺癌颈部淋巴结转移的发生密切相关，或可成为甲状腺癌侵袭性的预测因子。甲状腺癌超声造影增强模式与微血管密度的高低具有强相关性，微血管密度越高，侵袭性越强，为超声造影评估甲状腺癌侵袭性提供了病理学依据。在此基础上，建立人-机互助的甲状腺癌多特征可解释性的智能预测模型，通过传统多任务机器学习方法联合深度学习方法，对可疑甲状腺结节风险特征进行量化以提高超声诊断的准确性。②甲状腺癌细胞中有大量异形的线粒体。通过收集临床甲状腺癌组织（伴或不伴有淋巴结转移）、甲状腺癌细胞培养（乳头状癌细胞K1，未分化癌细胞8505C）及裸鼠成瘤等实验，结合分子生物学及蛋白组学定量技术等，发现在甲状腺癌细胞和组织标本中线粒体的分裂程度均较高，且线粒体分裂蛋白Drp1是甲状腺癌的生长和转移的重要特征，线粒体分裂抑制剂Mdivi-1通过NF-κB信号通路抑制甲状腺癌的上皮间质转化和增殖；而线粒体融合蛋白MFN2可能是甲状腺癌的抑癌基因，通过调节缺氧微环境抑制甲状腺癌细胞的上皮间质转化及增殖。本项目将超声影像图像特征与细胞内微观结构（细胞器、蛋白分子）相结合，揭示甲状腺癌低氧微环境特征及其线粒体动力学失衡调控缺氧微环境介导的肿瘤细胞增殖和侵袭，为甲状腺癌的精准治疗提供新的靶点。