Compensatory Function of Pyk2 Protein in the Promotion of Focal Adhesion Kinase (FAK)-null Mammary Cancer Stem Cell Tumorigenicity and Metastatic Activity
Compensatory Function of Pyk2 Protein in the Promotion of Focal Adhesion Kinase (FAK)-null Mammary Cancer Stem Cell Tumorigenicity and Metastatic Activity
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DOI：
10.1074/jbc.m110.200717
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发表时间：
2011-05-27
影响因子：
4.8
通讯作者：
Guan, Jun-Lin
中科院分区：
文献类型：
--
作者：
Fan, Huaping;Guan, Jun-Lin
乳腺癌干细胞（MaCSC）已被鉴定为能够自我更新以驱动乳腺肿瘤发生和转移的罕见细胞群体。尽管如此，人们对体内调节MaCSC自我更新和转移活性的细胞内信号通路知之甚少。使用最近开发的乳腺癌小鼠模型与粘着斑激酶（FAK）缺失的乳腺肿瘤细胞（MFCKO-MT小鼠），在这里，我们提出的证据表明Pyk 2，FAK相关的激酶，在调节MaCSC和转移在这些小鼠的代偿功能。在MFCKO-MT小鼠的肺转移结节中选择性地发现Pyk 2表达增加，并且其抑制显著降低了这些小鼠中乳腺肿瘤的发展和转移。与由MaCSC驱动的转移的想法一致，我们检测到在MFCKO-MT小鼠中发展的原发性肿瘤的MaCSC中Pyk 2的选择性上调，而不是大块乳腺肿瘤细胞。我们进一步表明，在FAK-无效的MaCSC中抑制Pyk 2显著降低了它们的体外肿瘤球形成和迁移以及体内自我更新、致瘤性和转移活性。最后，我们鉴定了PI 3 K/Akt信号传导作为FAK调节MaCSC的主要介质以及在FAK缺失的MaCSC中Pyk 2的补偿功能的靶标。总之，这些结果进一步推进了我们对FAK及其相关酪氨酸激酶Pyk 2在乳腺癌中调节MaCSC的理解，并表明药物靶向这些激酶可能有望通过靶向和根除MaCSC作为该疾病的新型治疗方法。
Mammary cancer stem cells (MaCSCs) have been identified as a rare population of cells capable of self-renewal to drive mammary tumorigenesis and metastasis. Nevertheless, relatively little is known about the intracellular signaling pathways regulating self-renewal and metastatic activities of MaCSCs in vivo. Using a recently developed breast cancer mouse model with focal adhesion kinase (FAK) deletion in mammary tumor cells (MFCKO-MT mice), here we present evidence suggesting a compensatory function of Pyk2, a FAK-related kinase, in the regulation of MaCSCs and metastasis in these mice. Increased expression of Pyk2 was found selectively in pulmonary metastatic nodules of MFCKO-MT mice, and its inhibition significantly reduced mammary tumor development and metastasis in these mice. Consistent with the idea of metastasis driven by MaCSCs, we detected selective up-regulation of Pyk2 in MaCSCs, but not bulk mammary tumor cells, of primary tumors developed in MFCKO-MT mice. We further showed that inhibition of Pyk2 in FAK-null MaCSCs significantly decreased their tumorsphere formation and migration in vitro as well as self-renewal, tumorigenicity, and metastatic activity in vivo. Last, we identified PI3K/Akt signaling as a major mediator of FAK regulation of MaCSCs as well as a target for the compensatory function of Pyk2 in FAK-null MaCSCs. Together, these results further advance our understanding of FAK and its related tyrosine kinase Pyk2 in regulation of MaCSCs in breast cancer and suggest that pharmaceutically targeting these kinases may hold promise as a novel treatment for the disease by targeting and eradicating MaCSCs.