Tumour Cell Biology Laboratory, The Francis Crick Institute, London, UK.
Department of Molecular Medicine, University of Padua, Padova, Italy.
Nat Cell Biol. 2020 Mar;22(3):289-296. doi: 10.1038/s41556-020-0474-3. Epub 2020 Feb 24.
The process of metastasis is complex. In breast cancer, there are frequently long time intervals between cells leaving the primary tumour and growth of overt metastases. Reasons for disease indolence and subsequent transition back to aggressive growth include interactions with myeloid and fibroblastic cells in the tumour microenvironment and ongoing immune surveillance. However, the signals that cause actively growing cells to enter an indolent state, thereby enabling them to survive for extended periods of time, are not well understood. Here we reveal how the behaviour of indolent breast cancer cells in the lung is determined by their interactions with alveolar epithelial cells, in particular alveolar type 1 cells. This promotes the formation of fibronectin fibrils by indolent cells that drive integrin-dependent pro-survival signals. Combined in vivo RNA sequencing and drop-out screening identified secreted frizzled-related protein 2 (SFRP2) as a key mediator of this interaction. Sfrp2 is induced in breast cancer cells by signals from lung epithelial cells and promotes fibronectin fibril formation and survival, whereas blockade of Sfrp2 expression reduces the burden of indolent disease.
转移的过程是复杂的。在乳腺癌中，细胞离开原发性肿瘤并生长为明显转移灶之间常常存在很长的时间间隔。导致疾病惰性和随后重新过渡到侵袭性生长的原因包括与肿瘤微环境中的髓样细胞和成纤维细胞的相互作用以及持续的免疫监视。然而，导致活跃生长的细胞进入惰性状态从而使它们能够存活很长时间的信号尚不清楚。在这里，我们揭示了惰性乳腺癌细胞在肺部的行为是如何由它们与肺泡上皮细胞，特别是肺泡 1 型细胞的相互作用决定的。这促进了由惰性细胞形成的纤连蛋白纤维的形成，从而驱动整合素依赖性存活信号。体内 RNA 测序和缺失筛选的组合确定分泌卷曲相关蛋白 2 (SFRP2) 是这种相互作用的关键介质。肺上皮细胞的信号诱导乳腺癌细胞中 Sfrp2 的表达，促进纤连蛋白纤维的形成和存活，而 Sfrp2 表达的阻断则降低惰性疾病的负担。
