Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells.
Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells.
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DOI：
10.1038/onc.2013.467
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发表时间：
2014-11-06
期刊：
影响因子：
8
通讯作者：
Avadhani NG
中科院分区：
文献类型：
--
作者：
Guha M;Srinivasan S;Ruthel G;Kashina AK;Carstens RP;Mendoza A;Khanna C;Van Winkle T;Avadhani NG
转移性乳腺肿瘤经历上皮到间质转化（EMT），这使得它们对针对原发癌症的治疗具有耐药性。mtDNA（线粒体DNA）减少（常见于乳腺癌患者）与EMT之间的机制联系尚不清楚。我们证明，减少人乳腺上皮细胞（hMECs）中mtDNA的含量可以激活钙调神经磷酸酶（Cn）依赖的线粒体逆行信号通路，从而诱导emt样重编程到成纤维细胞形态，细胞极性丧失，接触抑制和获得性迁移和侵袭表型。值得注意的是，mtDNA的减少产生了乳腺癌干细胞。除了逆行信号标记外，在这些细胞中还存在间充质基因的诱导，但上皮标记的丢失。这些变化可以通过恢复mtDNA含量或敲低CnAα mRNA来逆转，这表明逆行信号在EMT中的因果作用。我们的研究结果指出了一种针对线粒体逆行信号通路的转移性乳腺癌的新治疗策略，用于废除EMT和减弱逃避常规治疗的癌症干细胞。我们报道了一种新的调节机制，通过这种机制，低mtDNA含量在hmec中产生EMT和癌症干细胞。
Metastatic breast tumors undergo epithelial-to-mesenchymal transition (EMT), which renders them resistant to therapies targeted to the primary cancers. The mechanistic link between mtDNA (mitochondrial DNA) reduction, often seen in breast cancer patients, and EMT is unknown. We demonstrate that reducing mtDNA content in human mammary epithelial cells (hMECs) activates Calcineurin (Cn)-dependent mitochondrial retrograde signaling pathway, which induces EMT-like reprogramming to fibroblastic morphology, loss of cell polarity, contact inhibition and acquired migratory and invasive phenotype. Notably, mtDNA reduction generates breast cancer stem cells. In addition to retrograde signaling markers, there is an induction of mesenchymal genes but loss of epithelial markers in these cells. The changes are reversed by either restoring the mtDNA content or knockdown of CnAα mRNA, indicating the causal role of retrograde signaling in EMT. Our results point to a new therapeutic strategy for metastatic breast cancers targeted to the mitochondrial retrograde signaling pathway for abrogating EMT and attenuating cancer stem cells, which evade conventional therapies. We report a novel regulatory mechanism by which low mtDNA content generates EMT and cancer stem cells in hMECs.