Epigenomic profiling discovers trans-lineage SOX2 partnerships driving tumor heterogeneity in lung squamous cell carcinoma.
Epigenomic profiling discovers trans-lineage SOX2 partnerships driving tumor heterogeneity in lung squamous cell carcinoma.
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DOI：
10.1158/0008-5472.can-19-2132
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发表时间：
2019-09
期刊：
影响因子：
11.2
通讯作者：
Takashi Sato;S. Yoo;Ranran Kong;A. Sinha;P. Chandramani-Shivalingappa;Ayushi S. Patel;Maya Fridrikh;O. Nagano;T. Masuko;M. Beasley;C. Powell;Jun Zhu;H. Watanabe
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文献类型：
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作者：
Takashi Sato;S. Yoo;Ranran Kong;A. Sinha;P. Chandramani-Shivalingappa;Ayushi S. Patel;Maya Fridrikh;O. Nagano;T. Masuko;M. Beasley;C. Powell;Jun Zhu;H. Watanabe
作为肺癌的主要亚型之一，肺鳞状细胞癌(LUSC)的分子特征在过去几十年中并没有充分改善其非分层治疗策略。越来越多的证据表明，在癌症进化过程中，谱系特异的转录调节因子控制着分化状态，并奠定了它们不同的生物学行为。在这项研究中，通过研究LUSC的超级增强子环境，我们鉴定了一个先前未描述的由Sox2和神经谱系因子Brn2定义的‘神经’亚型，以及由Sox2和它的经典鳞状伴侣p63定义的经典LUSC亚型。在经典的LUSC中，Sox2和Brn2取代了p63，强大的蛋白质-蛋白质相互作用和基因组共占表明它们在转录上的合作赋予了“神经”LUSC这种独特的谱系状态。P63的强制表达下调了LUSC细胞中Brn2的表达，使LUSC的典型谱系具有更多的鳞状/上皮特征，同时伴随着ErbB/Akt和MAPK-ERK通路活性的增加，表明存在不同的依赖性。总而言之，我们的数据显示了以Sox2与Brn2或p63合作为特征的LUSC的异质性细胞谱系状态，对于这些情况，可能需要不同的治疗方法。
Molecular characterization of lung squamous cell carcinoma (LUSC), one of the major subtypes of lung cancer, has not sufficiently improved its non-stratified treatment strategies over decades. Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states during cancer evolution, and underlie their distinct biological behaviors. In this study, by investigating the super-enhancer landscape of LUSC, we identified a previously undescribed 'neural' subtype defined by Sox2 and a neural lineage factor Brn2, as well as the classical LUSC subtype defined by Sox2 and its classical squamous partner p63. Robust protein-protein interaction and genomic co-occupancy of Sox2 and Brn2, in place for p63 in the classical LUSC, indicated their transcriptional cooperation imparting this unique lineage state in the 'neural' LUSC. Forced expression of p63 downregulated Brn2 in the 'neural' LUSC cells and invoked the classical LUSC lineage with more squamous/epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK-ERK pathways suggesting differential dependency. Collectively, our data demonstrate heterogeneous cell lineage states of LUSC featured by Sox2 cooperation with Brn2 or p63, for which distinct therapeutic approaches may be warranted.