PO.TB10.07 · 肿瘤生物学
空间架构分析揭示淋巴毒素信号梯度紊乱与高级别浆液性卵巢癌复发相关
Spatial architecture analysis reveals disrupted lymphotoxin signaling gradients associate with recurrence in high-grade serous ovarian cancer
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摘要 Abstract
中文摘要
背景：复发是卵巢癌患者死亡的驱动因素，肿瘤-基质信号相互作用在疾病进展中发挥关键作用。淋巴毒素家族信号通过肿瘤与基质区室之间的淋巴毒素-LTBR相互作用运作，协调趋化因子介导的免疫细胞募集。然而，现有研究关注的是表达水平而非这些信号网络的空间组织。我们旨在表征高级别浆液性卵巢癌（HGSC）中淋巴毒素信号的空间梯度模式，并确定空间组织特征是否能区分复发与非复发疾病。
方法：我们整合了跨越多个独立队列的公开亚细胞空间转录组学数据集，包含>100例HGSC患者和>250万个空间解析细胞。患者按2年无进展生存期分为复发组与非复发组。我们使用基于邻域的方法量化空间表达梯度，计算淋巴毒素家族基因（LTA、LTB、LTBR）及相关趋化因子的空间自相关和肿瘤边界相关表达模式。
结果：尽管表达水平相当，复发性HGSC表现出淋巴毒素信号空间组织的紊乱。LTB在复发肿瘤中显示出降低的空间自相关（-0.254对-0.320，p=0.029），表明有组织的空间表达模式的丧失。LTBR在复发样本中显示出减弱的肿瘤边界梯度（Spearman ρ=-0.121对-0.178，p=0.034），提示肿瘤-基质界面处空间信号架构的紊乱。LTB在复发病例中也表现出肿瘤边界富集的减弱（ρ=-0.010对0.070，p=0.055）。细胞组成和整体基因表达未显示出显著差异，证实驱动这些发现的是空间组织而非丰度。
结论：复发性HGSC中LTB/LTBR空间梯度的紊乱表明，免疫逃逸涉及超越表达水平变化的肿瘤-基质信号的空间失组织。这些发现提示，恢复空间趋化因子梯度的干预措施——例如工程化淋巴毒素递送或空间靶向的基质重编程——可能增强免疫浸润，值得作为预防卵巢癌复发的策略加以研究。
查看英文原文 English abstract
Background: Recurrence drives mortality in ovarian cancer patients, with tumor-stromal signaling interactions playing critical roles in disease progression. Lymphotoxin family signaling, operating through lymphotoxin-LTBR interactions between tumor and stromal compartments, orchestrates chemokine-mediated immune cell recruitment. However, existing studies have focused on expression levels rather than spatial organization of these signaling networks. We aimed to characterize spatial gradient patterns of lymphotoxin signaling in high-grade serous ovarian cancer (HGSC) and determine whether spatial organizational features distinguish recurrent from non-recurrent disease.
Methods: We integrated publicly available subcellular spatial transcriptomics datasets spanning multiple independent cohorts, comprising >100 HGSC patients and >2.5 million spatially resolved cells. Patients were stratified by 2-year progression-free survival into recurred versus non-recurred groups. We quantified spatial expression gradients using neighborhood-based approaches, calculating spatial autocorrelation and tumor boundary-associated expression patterns for lymphotoxin family genes (LTA, LTB, LTBR) and related chemokines.
Results: Recurrent HGSC exhibited disrupted spatial organization of lymphotoxin signaling despite comparable expression levels. LTB displayed reduced spatial autocorrelation in recurrent tumors (-0.254 vs -0.320, p=0.029), indicating loss of organized spatial expression patterns. LTBR showed attenuated tumor boundary gradients in recurrent samples (Spearman ρ=-0.121 vs -0.178, p=0.034), suggesting disrupted spatial signaling architecture at tumor-stromal interfaces. LTB also demonstrated diminished tumor boundary enrichment in recurrent cases (ρ=-0.010 vs 0.070, p=0.055). Cellular composition and overall gene expression showed no significant differences, confirming that spatial organization rather than abundance drives these findings.
Conclusion: Disrupted LTB/LTBR spatial gradients in recurrent HGSC indicate that immune evasion involves spatial disorganization of tumor-stromal signaling beyond expression-level changes. These findings suggest that interventions restoring spatial chemokine gradients-such as engineered lymphotoxin delivery or spatially-targeted stromal reprogramming-may enhance immune infiltration and warrant investigation as strategies to prevent ovarian cancer recurrence.
利益披露 Disclosure
Z. Zhang, None..
T. Lau, None..
C. Wang, None.