Ainiwaer Aizier, Qian Zhenwei, Wang Jianxun, Zhao Qi, Lu Yinying
Comprehensive Liver Cancer Center, The 5Th Medical Center of the PLA General Hospital, Beijing, China.
Peking University 302 Clinical Medical School, Beijing, 100039, China.
Discov Oncol. 2024 Nov 22;15(1):696. doi: 10.1007/s12672-024-01566-0.
The liver is the predominant metastatic site for diverse cancers, including pancreatic and colorectal cancers (CRC), etc. The high incidence of hepatic metastasis of pancreatic cancer is an important reason for its refractory and high mortality. Therefore, it is important to understand how metastatic pancreatic cancer affects the hepatic tumor immune microenvironment (TME) in patients. Here, we characterized the TME of liver metastases unique to pancreatic cancer by comparing them with CRC liver metastases. We integrated two single-cell RNA-seq (scRNA-seq) datasets including tumor samples of pancreatic cancer liver metastasis (P-LM), colorectal cancer liver metastasis (C-LM), primary pancreatic cancer (PP), primary colorectal cancer (PC), as well as samples of peripheral blood mono-nuclear cells (PBMC), adjacent normal pancreatic tissues (NPT), to better characterize the heterogeneities of the microenvironment of two kinds of liver metastases. We next performed comparative analysis on cellular compositions between P-LM and C-LM, found that Mph_SPP1, a subset of macrophages associated with angiogenesis and tumor invasion, was more enriched in the P-LM group, indicating this kind of macrophages provide a TME niche more vulnerable for pancreatic cancers. Analysis of the developmental trajectory implied that Mph_SPP1 may progressively be furnished with increased expression of genes regulating endothelium. Cell-cell communications analysis revealed that Mph_SPP1 potentially interacts with endothelial cells in P-LM via FN1/SPP1-ITGAV/ITGB1, implying this macrophage subset may construct an immunosuppressive TME for pancreatic cancer by regulating endothelial cells. We also found that Mph_SPP1 has a prognostic value in pancreatic adenocarcinoma that is not present in colon adenocarcinoma or rectum adenocarcinoma. This study provides a new perspective for understanding the characteristics of the hepatic TME in patients with liver metastatic cancer. And it provides a subset of macrophages specifically associated with the liver metastasis of pancreatic cancer, and its detection and intervention have potential value for preventing the metastasis of pancreatic cancer to the liver.
肝脏是多种癌症的主要转移部位，包括胰腺癌和结直肠癌（CRC）等。胰腺癌肝转移的高发生率是其难治性和高死亡率的重要原因。因此，了解转移性胰腺癌如何影响患者的肝脏肿瘤免疫微环境（TME）非常重要。在此，我们通过将胰腺癌肝转移与CRC肝转移进行比较，对胰腺癌特有的肝转移TME进行了表征。我们整合了两个单细胞RNA测序（scRNA-seq）数据集，包括胰腺癌肝转移（P-LM）、结直肠癌肝转移（C-LM）、原发性胰腺癌（PP）、原发性结直肠癌（PC）的肿瘤样本，以及外周血单核细胞（PBMC）、相邻正常胰腺组织（NPT）的样本，以更好地表征两种肝转移微环境的异质性。接下来，我们对P-LM和C-LM之间的细胞组成进行了比较分析，发现与血管生成和肿瘤侵袭相关的巨噬细胞亚群Mph_SPP1在P-LM组中更为富集，表明这种巨噬细胞为胰腺癌提供了一个更易受影响的TME生态位。对发育轨迹的分析表明，Mph_SPP1可能会逐渐增加调节内皮细胞的基因表达。细胞间通讯分析显示，Mph_SPP1可能通过FN1/SPP1-ITGAV/ITGB1在P-LM中与内皮细胞相互作用，这意味着该巨噬细胞亚群可能通过调节内皮细胞为胰腺癌构建免疫抑制性TME。我们还发现，Mph_SPP1在胰腺腺癌中具有预后价值，而在结肠腺癌或直肠腺癌中不存在。本研究为理解肝转移癌患者肝脏TME的特征提供了新的视角。并且它提供了一个与胰腺癌肝转移特异性相关的巨噬细胞亚群，其检测和干预对预防胰腺癌肝转移具有潜在价值。
