Epidermal growth factor receptor (EGFR) is frequently amplified, mutated and overexpressed in malignant gliomas. Yet the EGFR-targeted therapies have thus far produced only marginal clinical response, and the underlying mechanism remains poorly understood. Through analyses of an inducible oncogenic EGFR-driven glioma mouse model system, our current study reveals a small population of glioma cells that can evade therapy-initiated apoptosis and potentiate relapse development by adopting a mesenchymal-like phenotypic state that no longer depends on oncogenic EGFR signaling. Transcriptome analyses of proximal and distal treatment responses further identify TGFβ/YAP/Slug signaling cascade activation as major regulatory mechanism that promotes therapy-induced glioma mesenchymal lineage transdifferentiation. Following anti-EGFR treatment, the TGFβ secreted from the stressed glioma cells acts to promote YAP nuclear translocation and activation, which subsequently stimulates upregulation of the pro-mesenchymal transcriptional factor Slug and then glioma lineage transdifferentiation towards a stable therapy-refractory state. Blockade of this adaptive response through enforced dominant negative YAP expression significantly delayed anti-EGFR relapse and significantly prolonged animal survival. Together, our findings shed new insight into EGFR-targeted therapy resistance and suggest that combinatorial therapies of targeting both EGFR and mechanisms underlying glioma lineage transdifferentiation could ultimately lead to deeper and more durable responses. Significance: This study demonstrates that molecular reprogramming and lineage transdifferentiation underlie anti-EGFR therapy resistance and is clinically relevant to the development of new combinatorial targeting strategies against malignant gliomas carrying aberrant EGFR signaling.

中文翻译：

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治疗诱导的转分化促进神经胶质瘤的生长，独立于EGFR信号传导

表皮生长因子受体（EGFR）在恶性神经胶质瘤中经常被扩增，突变和过表达。迄今为止，以EGFR为靶标的疗法仅产生了少量的临床反应，其潜在机制仍知之甚少。通过对可诱导的致癌性EGFR驱动的神经胶质瘤小鼠模型系统的分析，我们的当前研究揭示了少数神经胶质瘤细胞可以通过采用不再依赖致癌性EGFR的间充质样表型来逃避治疗引发的凋亡并增强复发发展信号。对近端和远端治疗反应的转录组分析进一步确定了TGFβ/ YAP / Slug信号级联激活是促进治疗诱导的神经胶质瘤间充质谱系转分化的主要调控机制。经过抗EGFR治疗后，应激神经胶质瘤细胞分泌的TGFβ起到促进YAP核易位和激活的作用，继而刺激间充质前转录因子Slug的上调，然后刺激神经胶质瘤谱系向分化至稳定的治疗难治性状态。通过强制显性负YAP表达来阻断这种适应性反应，显着延迟了抗EGFR的复发，并显着延长了动物的存活时间。在一起，我们的发现为针对EGFR的治疗耐药性提供了新的见识，并表明针对EGFR和神经胶质瘤谱系转分化基础机制的组合疗法最终可能导致更深，更持久的反应。意义：