PO.TB10.15 · 肿瘤生物学
代谢物驱动的翻译后修饰调控胶质母细胞瘤微环境中的线粒体稳态
Metabolite-driven post-translational modifications regulate mitochondrial homeostasis in the glioblastoma microenvironment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胶质母细胞瘤（GBM）是一种高度侵袭性的脑肿瘤，预后极差，亟需新的治疗策略。治疗 GBM 的一个关键挑战是肿瘤细胞与周围肿瘤微环境（TME）之间复杂的通讯，这增强了肿瘤的抵抗力。本研究探讨了由于癌症代谢改变而在 TME 中富集的代谢物如何影响 GBM 中的细胞间通讯和线粒体动力学。我们假设，由这些代谢物驱动的特定翻译后修饰（PTMs）调控线粒体稳态和功能，从而促进肿瘤进展。为验证这一假设，我们采用了一系列实验方法。建立了共培养系统以模拟 TME 内 GBM 细胞与基质细胞之间的相互作用。我们利用流式细胞术分析细胞特征和相互作用，同时使用 Western 印迹和免疫荧光检测蛋白质表达、定位和 PTMs。进行了功能测定，包括各种商用试剂盒，以评估线粒体生物学。开展了生物信息学分析以确定所涉及的潜在分子通路，并使用动物模型在体内验证了这些发现。我们尚未发表的数据揭示，某种特定肿瘤代谢物的异常增加导致关键蛋白质的 PTM。这种修饰改变了这些蛋白质的功能和表达，导致 GBM 细胞与基质细胞之间的相互作用增强。因此，我们观察到 GBM 细胞内线粒体相关生物学功能的增强，这最终推动了肿瘤进展。总之，我们的发现表明，GBM 微环境中的代谢副产物充当信号分子，有效地「劫持」正常基质细胞以支持肿瘤的线粒体稳态和生长。这种新的细胞间通讯机制为 GBM 病理生理学提供了一个潜在的新轴，为破坏肿瘤进展和改善患者预后提供了有前景的治疗靶点。
查看英文原文 English abstract
Glioblastoma (GBM) is a highly aggressive brain tumor with a dismal prognosis, demanding new therapeutic strategies. A key challenge in treating GBM is the complex communication between tumor cells and the surrounding tumor microenvironment (TME), which enhances tumor resilience. This study investigated how metabolites, abundant in the TME due to altered cancer metabolism, influence intercellular communication and mitochondrial dynamics in GBM. We hypothesized that specific post-translational modifications (PTMs), driven by these metabolites, regulate mitochondrial homeostasis and function, thereby promoting tumor progression. To test this hypothesis, we employed a range of experimental procedures. Co-culture systems were established to model the interaction between GBM cells and stromal cells within the TME. We utilized flow cytometry to analyze cellular characteristics and interactions, while Western blotting and immunofluorescence were used to examine protein expression, localization, and PTMs. Functional assays, including various commercial kits, were performed to assess mitochondrial biology. Bioinformatics analyses were conducted to identify potential molecular pathways involved, and these findings were validated in vivo using animal models. Our unpublished data reveal that an abnormal increase in a specific tumor metabolite leads to the PTM of key proteins. This modification alters the function and expression of these proteins, resulting in heightened interaction between GBM cells and stromal cells. Consequently, we observed an enhancement of mitochondrial-related biological functions within the GBM cells, which ultimately fuels tumor progression. In conclusion, our findings demonstrate that metabolic byproducts in the GBM microenvironment act as signaling molecules, effectively "hijacking" normal stromal cells to support the mitochondrial homeostasis and growth of the tumor. This novel mechanism of intercellular communication presents a potential new axis in GBM pathophysiology, offering promising therapeutic targets to disrupt tumor progression and improve patient outcomes.
利益披露 Disclosure
Z. You, None..
K. Kiang, None..
G. Leung, None.