Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis.
Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis.
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DOI：
10.15252/emmm.201809003
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发表时间：
2018-10
影响因子：
11.1
通讯作者：
Oskarsson T
中科院分区：
文献类型：
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作者：
Insua-Rodríguez J;Pein M;Hongu T;Meier J;Descot A;Lowy CM;De Braekeleer E;Sinn HP;Spaich S;Sütterlin M;Schneeweiss A;Oskarsson T
转移性进展仍然是癌症患者的主要负担，并且与对流行疗法（例如化疗）的最终抗性相关。在这里，我们揭示了化疗如何通过c-Jun N-末端激酶（JNK）途径诱导癌细胞中的细胞外基质（ECM），伤口愈合和干细胞网络，导致治疗效果降低。我们发现，癌细胞中JNK活性升高与乳腺癌患者的不良临床结局有关，并且对于乳腺癌异种移植小鼠模型中的肿瘤起始和转移至关重要。我们发现JNK信号增强了ECM和干细胞龛组分骨桥蛋白（也称为分泌型磷蛋白1（SPP 1））和腱生蛋白C（TNC）的表达，它们促进了肺转移。我们证明SPP 1和TNC都是c-Jun转录因子的直接靶点。暴露于多种化疗进一步利用JNK介导的轴来赋予治疗抗性。重要的是，JNK抑制或SPP 1或TNC表达的破坏使实验性乳腺肿瘤和转移灶对化疗敏感，从而为考虑未来针对转移性乳腺癌的治疗策略提供了见解。
Metastatic progression remains a major burden for cancer patients and is associated with eventual resistance to prevailing therapies such as chemotherapy. Here, we reveal how chemotherapy induces an extracellular matrix (ECM), wound healing, and stem cell network in cancer cells via the c‐Jun N‐terminal kinase (JNK) pathway, leading to reduced therapeutic efficacy. We find that elevated JNK activity in cancer cells is linked to poor clinical outcome in breast cancer patients and is critical for tumor initiation and metastasis in xenograft mouse models of breast cancer. We show that JNK signaling enhances expression of the ECM and stem cell niche components osteopontin, also called secreted phosphoprotein 1 (SPP1), and tenascin C (TNC), that promote lung metastasis. We demonstrate that both SPP1 and TNC are direct targets of the c‐Jun transcription factor. Exposure to multiple chemotherapies further exploits this JNK‐mediated axis to confer treatment resistance. Importantly, JNK inhibition or disruption of SPP1 or TNC expression sensitizes experimental mammary tumors and metastases to chemotherapy, thus providing insights to consider for future treatment strategies against metastatic breast cancer.