AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma.
AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma.
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DOI：
10.1038/s41467-020-18762-5
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发表时间：
2020-10-08
影响因子：
16.6
通讯作者：
Oro AE
中科院分区：
文献类型：
--
作者：
Yao CD;Haensel D;Gaddam S;Patel T;Atwood SX;Sarin KY;Whitson RJ;McKellar S;Shankar G;Aasi S;Rieger K;Oro AE
肿瘤异质性和缺乏对耐药细胞状态的了解仍然是靶向癌症治疗的障碍。基底细胞癌（BCC）依赖于Hedgehog（Hh）/Gli信号传导，但可发展Smoothened（SMO）抑制剂抗性机制。我们以前确定了一个核心肌蛋白相关转录因子（nMRTF）的阻力途径，放大非经典的Gli 1活性，但nMRTF细胞状态的特点和驱动程序仍然未知。在这里，我们使用患者肿瘤的单细胞RNA测序来鉴定与nMRTF和对SMO抑制剂的耐药性相关的三种预后表面标志物（LYPD 3、TACSTD 2和LY 6D）。nMRTF细胞状态类似于毛囊基质的传递放大细胞，AP-1和TGF β协同驱动nMRTF活化。JNK/AP-1信号转导委员会染色质可及性和Smad 3 DNA结合，导致促进nMRTF活性的RhoGEFs的转录程序。重要的是，小分子AP-1抑制剂选择性地离体靶向LYPD 3 +/TACSTD 2 +/LY 6D + nMRTF人BCC，为改善组合疗法开辟了途径。具有增加的核心肌蛋白相关转录因子（nMRTF）水平的基底细胞癌（BCC）细胞对Smoothened抑制剂具有抗性，然而MRTF活性如何被调节仍然是难以捉摸的。在这里，作者鉴定了耐药BCC细胞的LYPD 3 +/TACSTD 2 +/LY 6D + BCC亚群，其中AP-1和TGF β驱动nMRTF活化并扩增非典型Gli 1活性
Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFß cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies. Basal cell carcinoma (BCC) cells with increased nuclear myocardin-related transcription factor (nMRTF) levels are resistant to Smoothened inhibitors, however how MRTF activity is regulated is still elusive. Here, the authors identify a LYPD3+/TACSTD2+/LY6D+ BCC subpopulation of resistant BCC cells where AP-1 and TGFß drive nMRTF activation and amplify noncanonical Gli1 activity
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
23.9
作者：
Adam RC;Yang H;Ge Y;Lien WH;Wang P;Zhao Y;Polak L;Levorse J;Baksh SC;Zheng D;Fuchs E
通讯作者：
Fuchs E
DOI：
10.1083/jcb.129.6.1677
发表时间：
1995-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Brakenhoff RH;Gerretsen M;Knippels EM;van Dijk M;van Essen H;Weghuis DO;Sinke RJ;Snow GB;van Dongen GA
通讯作者：
van Dongen GA
影响因子：
11.5
作者：
Axelson, Michael;Liu, Ke;Pazdur, Richard
通讯作者：
Pazdur, Richard