Hepatobiliary Surgery Department, Yangzhou University Affiliated Hospital, Yangzhou, 225000, Jiangsu, China.
Medical College of Yangzhou University, Yangzhou, 225000, Jiangsu, China.
J Cancer Res Clin Oncol. 2023 Oct;149(13):11571-11584. doi: 10.1007/s00432-023-05015-3. Epub 2023 Jul 4.
Vascular mimicry (VM) epitomizes an innovative tumor angiogenesis pathway, potentially serving as an alternate conduit under the assumption of traditional tumor angiogenesis pathway inhibition. The role of VM in pancreatic cancer (PC), however, remains unexplored.
Using differential analysis and Spearman correlation, we identified key long non-coding RNAs (lncRNAs) signatures in PC from the collected set of VM-associated genes in the literature. We identified optimal clusters using the non-negative matrix decomposition (NMF) algorithm, and then compared clinicopathological features and prognostic differences between clusters. We also assessed tumor microenvironmental (TME) differences between clusters using multiple algorithms. Using univariate Cox regression analyses as well as lasso regression, we constructed and validated new lncRNA prognostic risk models for PC. We used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to analyze model-enriched functions and pathways. Nomograms were then developed to predict patient survival in association with clinicopathological factors. In addition, single-cell RNA-sequencing (scRNA-seq) analysis was used to analyze the expression patterns of VM-related genes and lncRNAs in the PC of TME. Finally, we used the Connectivity Map (cMap) database to predict local anaesthetics that could modify the VM of PC.
In this study, we developed a novel three-cluster molecular subtype using the identified VM-associated lncRNA signatures of PC. The different subtypes have significantly different clinical characteristics and prognostic value, and also show differential treatment response and TME. Following an in-depth analysis, we constructed and validated a novel prognostic risk model for PC based on the VM-associated lncRNA signatures. Enrichment analysis suggested that high riskscores were significantly associated with functions and pathways, including extracellular matrix remodeling, et al. In addition, we predicted eight local anaesthetics that could modulate VM in PC. Finally, we discovered differential expression of VM-related genes and lncRNAs across various cell types within pancreatic cancer.
VM has a critical role in PC. This study pioneers the development of a VM-based molecular subtype that demonstrates substantial differentiation in PC populations. Furthermore, we highlighted the significance of VM within the immune microenvironment of PC. Moreover, VM might contribute to PC tumorigenesis through its mediation of mesenchymal remodeling and endothelial transdifferentiation-related pathways, which offers a new perspective on its role in PC.
血管拟态（VM）体现了一种创新的肿瘤血管生成途径，假设传统的肿瘤血管生成途径被抑制，它可能作为一种替代途径。然而，VM 在胰腺癌（PC）中的作用仍未被探索。
使用差异分析和 Spearman 相关性，我们从文献中收集的与 VM 相关的基因中鉴定出 PC 中关键的长非编码 RNA（lncRNA）特征。我们使用非负矩阵分解（NMF）算法识别最优簇，然后比较簇间的临床病理特征和预后差异。我们还使用多种算法评估簇间的肿瘤微环境（TME）差异。使用单变量 Cox 回归分析和套索回归，我们构建和验证了用于 PC 的新 lncRNA 预后风险模型。我们使用基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析模型富集的功能和途径。然后开发列线图来预测与临床病理因素相关的患者生存情况。此外，还使用单细胞 RNA 测序（scRNA-seq）分析来分析 TME 中 VM 相关基因和 lncRNA 的表达模式。最后，我们使用 Connectivity Map（cMap）数据库来预测可以修饰 PC 的 VM 的局部麻醉剂。
在这项研究中，我们使用鉴定出的 PC 中与 VM 相关的 lncRNA 特征开发了一种新的三簇分子亚型。不同的亚型具有明显不同的临床特征和预后价值，并且还表现出不同的治疗反应和 TME。经过深入分析，我们基于与 VM 相关的 lncRNA 特征构建和验证了用于 PC 的新型预后风险模型。富集分析表明，高风险评分与包括细胞外基质重塑在内的功能和途径显著相关，等等。此外，我们预测了八种可以调节 PC 中 VM 的局部麻醉剂。最后，我们发现了 VM 相关基因和 lncRNA 在胰腺癌不同细胞类型中的差异表达。
VM 在 PC 中具有关键作用。本研究开创了基于 VM 的分子亚型的发展，该亚型在 PC 人群中表现出明显的差异。此外，我们强调了 VM 在 PC 免疫微环境中的重要性。此外，VM 可能通过调节间质重塑和内皮转分化相关途径促进 PC 肿瘤发生，这为其在 PC 中的作用提供了新的视角。
