MALT1 signaling network in B cell metabolism and function

癌细胞通常的特征在于高度需要生物合成前体分子和能量来驱动恶性增殖。然而，在B细胞淋巴瘤中，亚实体之间的代谢特征可能不同，反映了它们的遗传和生物学异质性。虽然目前还不清楚不同的致癌信号通路如何影响B细胞淋巴瘤代谢，但这些机制的鉴定可以为疾病分层和治疗靶点提供新的生物标志物。在以前的工作中，我们已经证明了CARD 11/BCL 10/MALT 1（CBM）复合物在生理和病理B细胞活化和淋巴瘤发生过程中的B细胞受体信号传导中起着至关重要的作用。此外，我们发现，从人弥漫性大B细胞淋巴瘤中分离的致癌CARD 11功能获得性突变的强制表达驱动了小鼠模型中的恶性B细胞过度增殖。我们还剖析了MALT 1效应蛋白在此过程中的不同贡献，并获得了该途径介导B细胞代谢重编程的证据。在这里，我们希望获得准确的机制的理解CBM依赖的代谢控制在正常和恶性B细胞的功能，并建立这些代谢功能如何有助于B细胞增殖，应激反应和生存。为此，我们将使用最先进的实验方法，如解吸电喷雾电离质谱（MSI）和快速蒸发电离质谱（REIMS），不仅研究细胞内代谢状态，而且还将我们的分析扩展到微环境。了解正常B细胞活化和致癌性硬连线B细胞如何影响其微环境的组成，也可能对微环境中旁观者细胞的功能产生广泛的影响。

Cancer cells are in general characterized by a high need for biosynthetic precursor molecules and energy to drive malignant proliferation. Nevertheless, in B cell lymphoma the metabolic signatures can differ between subentities reflecting their genetical and biological heterogeneity. While it is still largely unclear how distinct oncogenic signaling pathways shape B cell lymphoma metabolism, the identification of these mechanisms can provide new biomarkers for disease stratification and targets for treatment. In previous work, we have demonstrated that the CARD11/BCL10/MALT1 (CBM) complex plays crucial roles in B cell receptor signaling during physiological and pathologic B cell activation and in lymphomagenesis. Furthermore, we found that the enforced expression of an oncogenic CARD11 gain-of-function mutation, isolated from human diffuse large B cell lymphoma, drives malignant B cell hyperproliferation in murine models. We have also dissected the different contributions of the MALT1 effector protein during this process and obtained evidence that this pathway mediates B cell metabolic reprogramming. Here we want to gain precise mechanistic understanding of CBM-dependent metabolic control in normal and malignant B cell function and to establish how these metabolic features contribute to B cell proliferation, stress responses and survival. To this end, we will use state-of-the-art experimental methods such as desorption electrospray ionization mass spectrometry (DESI-MSI) and rapid evaporative ionization mass spectrometry (REIMS) not only to study intracellular metabolic states but also to extend our analysis to the microenvironment. Understanding how normal B cell activation and oncogenically hard-wired B cells affect the composition of their micromilieu could also have broad implications for the function of bystander cells in the micromilieu.