Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer.
Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer.
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DOI：
10.1038/s41467-018-05220-6
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发表时间：
2018-07-24
影响因子：
16.6
通讯作者：
Swarbrick A
中科院分区：
文献类型：
--
作者：
Cazet AS;Hui MN;Elsworth BL;Wu SZ;Roden D;Chan CL;Skhinas JN;Collot R;Yang J;Harvey K;Johan MZ;Cooper C;Nair R;Herrmann D;McFarland A;Deng N;Ruiz-Borrego M;Rojo F;Trigo JM;Bezares S;Caballero R;Lim E;Timpson P;O'Toole S;Watkins DN;Cox TR;Samuel MS;Martín M;Swarbrick A
对癌中基质细胞募集、活化和串扰的细胞和分子基础知之甚少，限制了靶向抗基质治疗的发展。在三阴性乳腺癌（TNBC）的小鼠模型中，由肿瘤细胞产生的Hedgehog配体重新编程癌症相关成纤维细胞（CAF），以通过FGF5表达和纤维状胶原蛋白的产生为获得化学抗性癌症干细胞（CSC）表型提供支持性小生境。用smoothened抑制剂（SMOi）对患者来源的异种移植物进行基质治疗可下调CSC标志物表达，并使肿瘤对多西他赛敏感，从而显著改善生存率并降低转移负荷。在I期临床试验EDALINE中，12例转移性TNBC患者中有3例从SMOi Sonidegib和多西他赛化疗的联合治疗中获得临床获益，其中1例患者完全缓解。这些研究将Hedgehog信号传导至CAFs作为CSC可塑性的新介质和TNBC中令人兴奋的新治疗靶点。基质细胞的募集、活化和与癌细胞的相互作用知之甚少。在这里，作者证明了癌细胞衍生的Hedgehog配体触发基质重塑，进而诱导附近癌细胞的癌症干细胞样耐药表型，而用smoothened抑制剂治疗逆转了这些表型。
The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC. Stromal cell recruitment, activation and crosstalk with cancer cells is poorly understood. Here, the authors demonstrate that cancer cell-derived Hedgehog ligand triggers stromal remodeling that in turn induces a cancer-stem-cell like, drug-resistant phenotype of nearby cancer cells while treatment with smoothened inhibitors reverses these phenotypes.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
癌症相关成纤维细胞通过旁分泌信号调节肺癌干细胞的可塑性
影响因子：
16.6
作者：
Chen, Wan-Jiun;Ho, Chao-Chi;Yang, Pan-Chyr
通讯作者：
Yang, Pan-Chyr
影响因子：
7.2
作者：
Hynes, Richard O.;Naba, Alexandra
通讯作者：
Naba, Alexandra
影响因子：
82.9
作者：
Farmer, Pierre;Bonnefoi, Herve;Delorenzi, Mauro
通讯作者：
Delorenzi, Mauro