PO.BCS01.09 · 生物信息与计算
溶酶体转运几何驱动三阴性乳腺癌中的免疫抑制性分泌
Lysosomal routing geometry drives immunosuppressive secretion in triple negative breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
三阴性乳腺癌（TNBC）显示出明显升高的分泌活性，这促成了高度免疫抑制的肿瘤微环境。溶酶体对降解和调节性分泌都至关重要，但其转运选择如何影响细胞因子释放尚未得到充分探索。为研究这一点，我们开发了一种亚细胞因果几何模型（SCGM），该模型映射纳米级溶酶体转运行为，并识别TNBC细胞中与免疫抑制性细胞因子产生相关的模式。SCGM整合了溶酶体蛋白质组学、LAMP1/LAMP2囊泡分布、RAB-GTPase相互作用谱以及来自患者样本的胞内pH梯度。使用几何感知Transformer对囊泡转运路径进行映射，揭示了若干模式。酸性微区域显得更为碎片化，V-ATPase活性发生偏移，RAB27A与LAMP1之间的相互作用以一致的方式发生变化。为确定这些变化的生物学影响，我们将其与细胞因子水平、巨噬细胞极化趋势、外泌体特征和干扰素反应标志物进行了比较。我们还对LAMP1、CTSB、ATP6V1C1、RAB27A和RAB7A进行了扰动模拟，并通过几何知情的Shapley排序评估其影响。这些发现揭示了三种不同的转运程序，包括分泌主导状态、降解状态和回收导向状态。分泌模式显示出碎片化的酸性微区域、RAB27A与LAMP1之间更强的相互作用以及更快的囊泡融合。与该状态相关的肿瘤释放出更高水平的TGF-beta1、IL-10、galectin-3和CXCL12（macro-AUC 0.95），并表现出近四倍高的M2样巨噬细胞极化以及降低的抗原提呈能力。扰动建模提示，降低RAB27A功能可将免疫抑制性细胞因子释放降低近三分之二。破坏LAMP1会破坏分泌转运框架的稳定性，而ATP6V1C1抑制使肿瘤转向更具免疫激活的表型。CTSB、RAB7A、ATP6V0A1以及LAMP1→RAB27A转变反复成为主要调控因子。综上所述，这些结果勾勒出一种此前未被认识的溶酶体转运结构，它塑造了TNBC中的免疫抑制性细胞因子释放，并指出溶酶体几何可作为重塑TNBC免疫环境的潜在生物标志物和干预点。
查看英文原文 English abstract
Triple-negative breast cancer (TNBC) shows markedly elevated secretory activity, which contributes to a highly immunosuppressive tumor microenvironment. Lysosomes are central to both degradation and regulated secretion, but how their routing choices influence cytokine release has not been well explored. To investigate this, we developed a Subcellular Causal Geometry Model (SCGM) that maps nanoscale lysosomal routing behavior and identifies patterns in TNBC cells associated with the production of immunosuppressive cytokines. SCGM brings together lysosomal proteomics, LAMP1/LAMP2 vesicle distributions, RAB-GTPase interaction profiles, and intracellular pH gradients derived from patient samples. The mapping of the vesicle-routing paths using a geometry-aware transformer revealed several patterns. Acidic microdomains appeared more fragmented, V-ATPase activity shifted, and the interaction between RAB27A and LAMP1 shifted in a consistent way. To determine the biological impact of these changes, we compared them with cytokine levels, trends in macrophage polarization, exosome characteristics, and interferon-response markers. We also ran perturbation simulations for LAMP1, CTSB, ATP6V1C1, RAB27A, and RAB7A, and evaluated their influence through a geometry-informed Shapley ranking. These findings revealed three distinct routing programs, including a secretory-dominant state, a degradative state, and a recycling-oriented state. The secretory pattern showed fragmented acidic microdomains, stronger interactions between RAB27A and LAMP1, and faster vesicle fusion. Tumors associated with this state released higher levels of TGF-beta1, IL-10, galectin-3, and CXCL12 (macro-AUC 0.95) and exhibited nearly fourfold higher M2-like macrophage polarization along with reduced antigen-presenting capacity. Perturbation modeling suggested that reducing RAB27A function could lower immunosuppressive cytokine release by almost two-thirds. Disrupting LAMP1 destabilized the secretory routing framework, and ATP6V1C1 inhibition shifted tumors toward a more immune-activating phenotype. CTSB, RAB7A, ATP6V0A1, and the LAMP1→RAB27A transition repeatedly emerged as major regulators. Taken together, these results outline an unrecognized lysosomal-routing architecture that shapes immunosuppressive cytokine release in TNBC and point to lysosomal geometry as a potential biomarker and intervention point for reshaping the TNBC immune environment.
利益披露 Disclosure
S. Sharma, None..
M. K. Mishra, None.