A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche that is composed of hematopoietic cells, stromal cells and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesized that perivascular cells similarly regulate tumor cell fate at metastatic sites. We used perivascular-cell-specific and pericyte-specific lineage-tracing models to trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC and pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically switched perivascular cells promoted a less differentiated state, characterized by enhanced ECM production, that established a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreased formation of a pre-metastatic niche and metastasis. Our data revealed a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncovered novel strategies for limiting metastasis.

中文翻译：

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KLF4依赖性血管周细胞可塑性介导转移前的生态位形成和转移。

为了提高患者生存率的新疗法的发展，需要对转移过程有更深入的了解。通过形成由造血细胞，基质细胞和细胞外基质（ECM）组成的转移前小生境，可促进远处器官中转移性肿瘤细胞的生长和存活。包括血管平滑肌细胞（vSMC）和周细胞在内的血管周细胞参与新血管的形成，并促进干细胞的维持和增殖。考虑到血管周细胞的可塑性，我们假设血管周细胞在转移部位同样调节肿瘤细胞的命运。我们使用血管周细胞特​​异性和周细胞特异性谱系追踪模型来追踪转移前和转移性微环境中血管周细胞的命运。我们显示血管周细胞失去传统vSMC和周细胞标记物对肿瘤分泌因子的反应，并表现出增加的增殖，迁移和ECM合成。在这些表型转换的血管周细胞中多能性基因Klf4表达的增加促进了分化程度较低的状态，其特征是增强了ECM的产生，从而建立了富转移性纤连蛋白的环境。血管周细胞中Klf4的基因失活减少了转移前小生境和转移的形成。我们的数据揭示了血管周细胞在转移前小生境形成中的作用尚未确定，并发现了限制转移的新策略。