Weitz Jonathan, Garg Bharti, Tiriac Herve, Martsinkovskiy Alexei, Patel Sandip, Lowy Andrew
University of California San Diego.
Res Sq. 2023 Mar 28:rs.3.rs-2715023. doi: 10.21203/rs.3.rs-2715023/v1.
Perineural invasion (PNI) is the phenomenon whereby cancer cells invade the space surrounding nerves. PNI occurs frequently in epithelial malignancies, but is especially characteristic of pancreatic ductal adenocarcinoma (PDAC). The presence of PNI portends an increased incidence of local recurrence, metastasis and poorer overall survival. While interactions between tumor cells and nerves have been investigated, the etiology and initiating cues for PNI development is not well understood. Here, we used digital spatial profiling to reveal changes in the transcriptome and to allow for a functional analysis of neural-supportive cell types present within the tumor-nerve microenvironment of PDAC during PNI. We found that hypertrophic tumor-associated nerves within PDAC express transcriptomic signals of nerve damage including programmed cell death, Schwann cell proliferation signaling pathways, as well as macrophage clearance of apoptotic cell debris by phagocytosis. Moreover, we identified that neural hypertrophic regions have increased local neuroglial cell proliferation which was tracked using EdU tumor labeling in KPC mice. This study reveals a common gene expression pattern that characterizes solid tumor-induced damage to local nerves. These data provide new insights into the pathobiology of the tumor-nerve microenvironment during PDAC as well as other gastrointestinal cancers.
神经周围浸润（PNI）是癌细胞侵入神经周围间隙的现象。PNI在上皮性恶性肿瘤中频繁发生，但在胰腺导管腺癌（PDAC）中尤为典型。PNI的存在预示着局部复发、转移的发生率增加以及总体生存率降低。虽然已经对肿瘤细胞与神经之间的相互作用进行了研究，但PNI发生发展的病因和起始线索尚未完全明确。在此，我们使用数字空间分析来揭示转录组的变化，并对PNI过程中PDAC肿瘤-神经微环境中存在的神经支持细胞类型进行功能分析。我们发现，PDAC内肥大的肿瘤相关神经表达神经损伤的转录组信号，包括程序性细胞死亡、雪旺细胞增殖信号通路，以及巨噬细胞通过吞噬作用清除凋亡细胞碎片。此外，我们发现神经肥大区域局部神经胶质细胞增殖增加，这在KPC小鼠中通过EdU肿瘤标记进行了追踪。这项研究揭示了一种共同的基因表达模式，其特征为实体瘤对局部神经造成损伤。这些数据为PDAC以及其他胃肠道癌症中肿瘤-神经微环境的病理生物学提供了新的见解。
