Department of Respiratory Oncology, Division of Life Sciences and Medicine, the First Affiliated Hospital of University of USTC, University of Science and Technology of China, Hefei, Anhui, China.
Department of Oncology, Division of Life Sciences and Medicine, the First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China.
Clin Transl Med. 2024 Mar;14(3):e1605. doi: 10.1002/ctm2.1605.
Bone or brain metastases may develop in 20-40% of individuals with late-stage non-small-cell lung cancer (NSCLC), resulting in a median overall survival of only 4-6 months. However, the primary lung cancer tissue's distinctions between bone, brain and intrapulmonary metastases of NSCLC at the single-cell level have not been underexplored.
We conducted a comprehensive analysis of 14 tissue biopsy samples obtained from treatment-naïve advanced NSCLC patients with bone (n = 4), brain (n = 6) or intrapulmonary (n = 4) metastasis using single-cell sequencing originating from the lungs. Following quality control and the removal of doublets, a total of 80 084 cells were successfully captured.
The most significant inter-group differences were observed in the fraction and function of fibroblasts. We identified three distinct cancer-associated fibroblast (CAF) subpopulations: myofibroblastic CAF (myCAF), inflammatory CAF (iCAF) and antigen-presenting CAF (apCAF). Notably, apCAF was prevalent in NSCLC with bone metastasis, while iCAF dominated in NSCLC with brain metastasis. Intercellular signalling network analysis revealed that apCAF may play a role in bone metastasis by activating signalling pathways associated with cancer stemness, such as SPP1-CD44 and SPP1-PTGER4. Conversely, iCAF was found to promote brain metastasis by activating invasion and metastasis-related molecules, such as MET hepatocyte growth factor. Furthermore, the interaction between CAFs and tumour cells influenced T-cell exhaustion and signalling pathways within the tumour microenvironment.
This study unveils the direct interplay between tumour cells and CAFs in NSCLC with bone or brain metastasis and identifies potential therapeutic targets for inhibiting metastasis by disrupting these critical cell-cell interactions.
晚期非小细胞肺癌（NSCLC）患者中有 20-40%会发生骨或脑转移，导致中位总生存期仅为 4-6 个月。然而，在单细胞水平上，NSCLC 的骨、脑和肺内转移的原发性肺癌组织之间的区别尚未得到充分探索。
我们对 14 例未经治疗的晚期 NSCLC 患者的骨（n=4）、脑（n=6）或肺内（n=4）转移的组织活检样本进行了单细胞测序分析。经过质量控制和去除双细胞后，成功捕获了 80084 个细胞。
各组之间最显著的差异是成纤维细胞的比例和功能。我们鉴定出三种不同的癌相关成纤维细胞（CAF）亚群：肌成纤维 CAF（myCAF）、炎性 CAF（iCAF）和抗原呈递 CAF（apCAF）。值得注意的是，apCAF 在伴有骨转移的 NSCLC 中较为常见，而 iCAF 在伴有脑转移的 NSCLC 中占主导地位。细胞间信号网络分析表明，apCAF 通过激活与癌症干性相关的信号通路，如 SPP1-CD44 和 SPP1-PTGER4，可能在骨转移中发挥作用。相反，iCAF 被发现通过激活侵袭和转移相关分子，如 MET 肝细胞生长因子，促进脑转移。此外，CAF 与肿瘤细胞之间的相互作用影响肿瘤微环境中的 T 细胞耗竭和信号通路。
本研究揭示了 NSCLC 伴骨或脑转移中肿瘤细胞与 CAF 之间的直接相互作用，并确定了通过破坏这些关键细胞-细胞相互作用来抑制转移的潜在治疗靶点。
