Seip Kotryna, Fleten Karianne G, Barkovskaya Anna, Nygaard Vigdis, Haugen Mads H, Engesæter Birgit Ø, Mælandsmo Gunhild M, Prasmickaite Lina
Department of Tumor Biology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Oncotarget. 2016 Apr 12;7(15):19997-20015. doi: 10.18632/oncotarget.7671.
The knowledge on how tumor-associated stroma influences efficacy of anti-cancer therapy just started to emerge. Here we show that lung fibroblasts reduce melanoma sensitivity to the BRAF inhibitor (BRAFi) vemurafenib only if the two cell types are in close proximity. In the presence of fibroblasts, the adjacent melanoma cells acquire de-differentiated mesenchymal-like phenotype. Upon treatment with BRAFi, such melanoma cells maintain high levels of phospho ribosomal protein S6 (pS6), i.e. active mTOR signaling, which is suppressed in the BRAFi sensitive cells without stromal contacts. Inhibitors of PI3K/mTOR in combination with BRAFi eradicate pS6high cell subpopulations and potentiate anti-cancer effects in melanoma protected by the fibroblasts. mTOR and BRAF co-inhibition also delayed the development of early-stage lung metastases in vivo. In conclusion, we demonstrate that upon influence from fibroblasts, melanoma cells undergo a phenotype switch to the mesenchymal state, which can support PI3K/mTOR signaling. The lost sensitivity to BRAFi in such cells can be overcome by co-targeting PI3K/mTOR. This knowledge could be explored for designing BRAFi combination therapies aiming to eliminate both stroma-protected and non-protected counterparts of metastases.
关于肿瘤相关基质如何影响抗癌治疗效果的知识才刚刚开始显现。在此我们表明，只有当肺成纤维细胞与黑素瘤细胞紧密相邻时，肺成纤维细胞才会降低黑素瘤对BRAF抑制剂（BRAFi）维莫非尼的敏感性。在存在成纤维细胞的情况下，相邻的黑素瘤细胞会获得去分化的间充质样表型。在用BRAFi治疗后，此类黑素瘤细胞维持高水平的磷酸化核糖体蛋白S6（pS6），即活跃的mTOR信号传导，而在没有基质接触的BRAFi敏感细胞中该信号传导被抑制。PI3K/mTOR抑制剂与BRAFi联合使用可根除pS6高表达的细胞亚群，并增强在成纤维细胞保护下的黑素瘤的抗癌效果。mTOR和BRAF共同抑制在体内也延迟了早期肺转移的发展。总之，我们证明，在成纤维细胞的影响下，黑素瘤细胞会发生表型转换为间充质状态，这可以支持PI3K/mTOR信号传导。通过共同靶向PI3K/mTOR可以克服此类细胞对BRAFi丧失的敏感性。这一知识可用于设计BRAFi联合疗法，旨在消除转移灶中受基质保护和未受保护的对应细胞。
