Høye Eirik, Kanduri Chakravarthi, Torgunrud Annette, Lorenz Susanne, Edwin Bjørn, Larsen Stein G, Fretland Åsmund A, Dagenborg Vegar J, Flatmark Kjersti, Lund-Andersen Christin
Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Cancer Med. 2025 Jan;14(1):e70521. doi: 10.1002/cam4.70521.
Metastatic colorectal cancer (mCRC) is the main cause of CRC mortality, with limited treatment options. Although immunotherapy has benefited some cancer patients, mCRC typically lacks the molecular features that respond to this treatment. However, recent studies indicate that the immune microenvironment of mCRC may be modified to enhance the effect of immune checkpoint inhibitors. This study aimed to explore the metastatic tumor microenvironment (TME) by comparing cell populations in colorectal liver (CLM), lung (mLu), and peritoneal (PM) metastases.
RNA isolated from 20 CLM, 15 mLu, and 35 PM samples was subjected to mRNA sequencing and explored through TME deconvolution tools, consensus molecular subtyping (CMS), and differential gene expression and gene set enrichment analysis, with respect to the metastatic sites. Clinical data and KRAS/BRAF hotspot mutation status were also obtained for all the cases.
The cell type fractions in the TME were relatively similar between the metastatic sites, except for cancer-associated fibroblasts (CAFs), B cells, endothelial cells, and CD4+ T cells. Notably, PM showed enrichment for CAFs and endothelial cells, consistent with distinct pathways associated with metastatic growth and progression in the peritoneal cavity. PM with the mesenchymal subtype, CMS4, had increased CAFs, endothelial cells, and macrophages, along with up-regulated genes related to TNF-α signaling via NF-κB, EMT, and angiogenesis.
Tumor samples from different metastatic sites exhibited a broadly similar TME in terms of immune cell composition, with some intriguing differences. Targeting CAF-associated pathways, macrophages, and TNF-α signaling through NR4A could represent potential novel therapeutic approaches in CMS4 PM.
转移性结直肠癌（mCRC）是结直肠癌死亡的主要原因，治疗选择有限。尽管免疫疗法使一些癌症患者受益，但mCRC通常缺乏对这种治疗有反应的分子特征。然而，最近的研究表明，mCRC的免疫微环境可能被改变以增强免疫检查点抑制剂的效果。本研究旨在通过比较结直肠癌肝转移（CLM）、肺转移（mLu）和腹膜转移（PM）中的细胞群来探索转移性肿瘤微环境（TME）。
从20个CLM、15个mLu和35个PM样本中分离出的RNA进行mRNA测序，并通过TME反卷积工具、共识分子亚型分析（CMS）以及差异基因表达和基因集富集分析来研究转移部位。还获取了所有病例的临床数据以及KRAS/BRAF热点突变状态。
除癌症相关成纤维细胞（CAF）、B细胞、内皮细胞和CD4 + T细胞外，TME中的细胞类型分数在转移部位之间相对相似。值得注意的是，PM显示出CAF和内皮细胞富集，这与腹膜腔中与转移生长和进展相关的不同途径一致。具有间充质亚型CMS4的PM中，CAF、内皮细胞和巨噬细胞增加，同时与通过NF-κB的TNF-α信号传导、上皮-间质转化（EMT）和血管生成相关的基因上调。
来自不同转移部位的肿瘤样本在免疫细胞组成方面表现出大致相似的TME，但存在一些有趣的差异。通过NR4A靶向CAF相关途径、巨噬细胞和TNF-α信号传导可能代表CMS4 PM中潜在的新型治疗方法。
