Spatial and Transcriptomic Analysis of Perineural Invasion in Oral Cancer.
Spatial and Transcriptomic Analysis of Perineural Invasion in Oral Cancer.
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DOI：
10.1158/1078-0432.ccr-21-4543
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发表时间：
2022-08-15
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神经浸润（PNI）是口腔鳞状细胞癌的常见现象，与生存率低有关。因此，这些肿瘤得到了积极的治疗。然而，PNI的诊断标准各不相同，其作为预后的独立预测因子的作用尚未确立。为了解决这些知识差距，我们研究了PNI阳性和PNI阴性神经的空间和转录组学特征。142例患者的组织切片用S100和细胞角蛋白抗体染色。在两个不同的区域确定了神经：肿瘤块和边缘。评估神经直径和神经到肿瘤的距离;进行生存分析。使用NanoString GeoMx Digital Spatial Profiler Transcriptomic Atlas对距肿瘤不同距离的神经进行空间转录组学分析。PNI是无淋巴结转移患者预后不良的独立预测因子。神经-肿瘤距离近的患者，即使使用当前标准诊断为PNI阴性，预后也较差。在肿瘤块中具有大神经的患者存活较差，这表明即使是PNI阴性神经也会促进肿瘤进展。诊断标准得到了超过18，000个基因的空间转录组学分析的支持;靠近癌症的神经表现出随着神经-肿瘤距离的增加而减少的应激和生长反应变化。这些发现在体外和人体组织中得到了验证。这是第一项在人类癌症中进行神经高通量基因表达分析的研究，其转录组学特征与临床结果之间存在显著相关性。我们的工作阐明了神经与癌症的相互作用，表明癌症引起的损伤调节了神经突的发生，并支持基于神经与肿瘤的距离而不是当前的主观标准对PNI进行重新分类。
Perineural invasion (PNI), a common occurrence in oral squamous cell carcinomas, is associated with poor survival. Consequently, these tumors are treated aggressively. However, diagnostic criteria of PNI vary and its role as an independent predictor of prognosis has not been established. To address these knowledge gaps, we investigated spatial and transcriptomic profiles of PNI-positive and PNI-negative nerves. Tissue sections from 142 patients were stained with S100 and cytokeratin antibodies. Nerves were identified in two distinct areas: tumor bulk and margin. Nerve diameter and nerve-to-tumor distance were assessed; survival analyses were performed. Spatial transcriptomic analysis of nerves at varying distances from tumor was performed with NanoString GeoMx Digital Spatial Profiler Transcriptomic Atlas. PNI is an independent predictor of poor prognosis among patients with metastasis-free lymph nodes. Patients with close nerve-tumor distance have poor outcomes even if diagnosed as PNI negative using current criteria. Patients with large nerve(s) in the tumor bulk survive poorly, suggesting that even PNI-negative nerves facilitate tumor progression. Diagnostic criteria were supported by spatial transcriptomic analyses of >18,000 genes; nerves in proximity to cancer exhibit stress and growth response changes that diminish with increasing nerve-tumor distance. These findings were validated in vitro and in human tissue. This is the first study in human cancer with high-throughput gene expression analysis in nerves with striking correlations between transcriptomic profile and clinical outcomes. Our work illuminates nerve-cancer interactions suggesting that cancer-induced injury modulates neuritogenesis, and supports reclassification of PNI based on nerve-tumor distance rather than current subjective criteria.