KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis.
KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis.
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DOI：
10.1038/nm.4400
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发表时间：
2017-10
期刊：
影响因子：
82.9
通讯作者：
Kaplan RN
中科院分区：
文献类型：
--
作者：
Murgai M;Ju W;Eason M;Kline J;Beury DW;Kaczanowska S;Miettinen MM;Kruhlak M;Lei H;Shern JF;Cherepanova OA;Owens GK;Kaplan RN
开发提高患者生存率的新疗法需要更深入地了解转移过程。由造血细胞、基质细胞和细胞外基质 (ECM) 组成的转移前生态位的形成促进了远处器官中转移性肿瘤细胞的生长和存活。血管周围细胞，包括血管平滑肌细胞（vSMC）和周细胞，参与新血管的形成以及促进干细胞的维持和增殖。鉴于血管周围细胞的可塑性，我们假设血管周围细胞类似地调节转移部位的肿瘤细胞命运。使用血管周围细胞特异性和周细胞特异性谱系追踪模型，我们追踪血管周围细胞在转移前和转移微环境中的命运。我们发现，血管周围细胞响应肿瘤分泌因子而失去传统 vSMC/周细胞标志物的表达，并表现出增殖、迁移和 ECM 合成增加。在这些表型转换的血管周围细胞中，多能性基因 Klf4 的表达增加会促进分化程度较低的状态，其特征是 ECM 产生增强，从而建立富含促转移纤连蛋白的环境。血管周围细胞中 Klf4 的基因失活会减少转移前生态位的形成和转移。我们的数据揭示了血管周围细胞在转移前生态位形成中先前未确定的作用，并揭示了限制转移的新策略。
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 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 hypothesize that perivascular cells similarly regulate tumor cell fate at metastatic sites. Using perivascular cell-specific and pericyte-specific lineage-tracing models, we trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC/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 promotes a less differentiated state characterized by enhanced ECM production that establishes a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreases pre-metastatic niche formation and metastasis. Our data reveal a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncover novel strategies for limiting metastasis.
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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
23.9
作者：
Hanoun, Maher;Zhang, Dachuan;Mizoguchi, Toshihide;Pinho, Sandra;Pierce, Halley;Kunisaki, Yuya;Lacombe, Julie;Armstrong, Scott A.;Duehrsen, Ulrich;Frenette, Paul S.
通讯作者：
Frenette, Paul S.
影响因子：
5.4
作者：
Goel, Shom;Wong, Andus Hon-Kit;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
影响因子：
15.9
作者：
Alexander, Matthew R.;Moehle, Christopher W.;Owens, Gary K.
通讯作者：
Owens, Gary K.
造血干/祖细胞的激活促进了替代前生态裂市场内的免疫抑制。
影响因子：
11.2
作者：
Giles AJ;Reid CM;Evans JD;Murgai M;Vicioso Y;Highfill SL;Kasai M;Vahdat L;Mackall CL;Lyden D;Wexler L;Kaplan RN
通讯作者：
Kaplan RN