Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Nature. 2022 Jun;606(7913):396-405. doi: 10.1038/s41586-022-04774-2. Epub 2022 Jun 1.
Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells-in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung.
原发肿瘤的癌细胞可以扩散到远处的组织，但可能需要数年时间才能形成明显的转移，这种现象被称为肿瘤休眠。尽管肿瘤休眠在转移和残留疾病中很重要，但很少有研究能够成功地对其进行特征描述。在这里，我们表明，衰老的肺部微环境为休眠的播散性癌细胞的有效生长提供了一个许可的龛位——与衰老的皮肤形成对比，衰老相关的变化抑制黑色素瘤的生长，但会促进其扩散。这些微环境的复杂性可以用表型转换模型来解释，该模型认为黑色素瘤细胞在增殖细胞状态和生长缓慢、侵袭性的状态之间转换。先前的研究表明，真皮成纤维细胞在衰老过程中促进黑色素瘤中的表型转换。我们现在发现 WNT5A 是肺内黑色素瘤播散性癌细胞休眠的激活剂，它最初使黑色素瘤细胞在转移龛位中有效地扩散和定植。肺成纤维细胞的年龄诱导重编程增加了它们分泌可溶性 WNT 拮抗剂 sFRP1 的能力，从而抑制了黑色素瘤细胞中的 WNT5A，从而使有效的转移性生长成为可能。我们还发现酪氨酸激酶受体 AXL 和 MER 促进了黑色素瘤细胞中的休眠-再激活轴。总的来说，我们发现远端转移性微环境的年龄诱导变化促进了肺部休眠黑色素瘤细胞的有效再激活。
