Hongu Tsunaki, Kusunoki Hirokazu, Ishimura Akihiko, Suzuki Takeshi, Oskarsson Thordur, Gotoh Noriko
Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan.
Institute for Frontier Science Initiative, Kanazawa University, Kanazawa City, Japan.
Cancer Sci. 2025 Jun;116(6):1604-1615. doi: 10.1111/cas.70050. Epub 2025 Apr 11.
Chemotherapy resistance remains a major obstacle for eradicating metastatic cancer cells in distant organs. We identified that endothelial cells (ECs) in the lungs, where breast cancer cells often metastasize, form a chemoresistant perivascular niche for disseminated breast cancer cells. By investigating the lung EC secretome activated by metastasis, we found that serine protease inhibitor family E member 1 (SERPINE1), encoded by Serpine1, is upregulated in metastasis-associated lung ECs. This upregulation shields cancer cells from paclitaxel-induced apoptosis and promotes cancer stem cell properties. Serpine1 expression appears to be driven by YAP-TEAD activation in lung ECs that lose cell-cell contact, a phenomenon associated with increased vascular permeability in lungs affected by metastasis. Crucially, pharmacological inhibition of SERPINE1 enhances the chemotherapy sensitivity of metastatic breast cancer cells in the lung. Overall, our findings underscore the pivotal role of the vascular niche, which produces SERPINE1, in conferring chemoresistance to breast cancer cells during metastatic progression in the lungs.
化疗耐药性仍然是根除远处器官中转移性癌细胞的主要障碍。我们发现，乳腺癌细胞常转移至肺部，肺部的内皮细胞（ECs）会为播散的乳腺癌细胞形成一个化疗耐药性的血管周围微环境。通过研究由转移激活的肺EC分泌组，我们发现Serpine1编码的丝氨酸蛋白酶抑制剂家族E成员1（SERPINE1）在与转移相关的肺EC中上调。这种上调使癌细胞免受紫杉醇诱导的细胞凋亡影响，并促进癌症干细胞特性。Serpine1的表达似乎是由失去细胞间接触的肺EC中的YAP-TEAD激活驱动的，这种现象与受转移影响的肺部血管通透性增加有关。至关重要的是，对SERPINE1的药理学抑制增强了肺中转移性乳腺癌细胞的化疗敏感性。总体而言，我们的研究结果强调了产生SERPINE1的血管微环境在肺部转移进展过程中赋予乳腺癌细胞化疗耐药性方面的关键作用。
