Oncogenic ERRB2 signals through the AP-1 transcription factor to control mesenchymal-like properties of oesophageal adenocarcinoma.
Oncogenic ERRB2 signals through the AP-1 transcription factor to control mesenchymal-like properties of oesophageal adenocarcinoma.
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食管腺癌（OAC）是一种致命的疾病，生存率统计数据不佳，且可用的靶向治疗很少。 OAC 最常见的分子异常之一是编码受体酪氨酸激酶 ERBB2 的基因扩增或激活，ERBB2 是临床上针对这部分患者的目标。然而，这些 ERBB2 激活事件的下游后果尚不清楚。在这里，我们结合使用磷酸蛋白质组学、开放染色质分析和细胞系模型和患者来源数据集的转录组分析来探究 ERBB2 下游的分子通路。这些数据集的综合分析集中在一个模型上，其中失调的 ERBB2 信号传导在转录水平上由转录因子 AP-1 介导。 AP-1 反过来通过作用于调节细胞迁移和粘附的基因组来控制细胞行为，这些特征通常与 EMT 相关。因此，我们的研究为癌细胞信号转导界提供了宝贵的资源，并揭示了 OAC 细胞失调行为背后的新分子决定因素。致癌 ERBB2 信号通过激活 AP-1 转录因子，进而激活类似 EMT 的基因表达程序，从而从潜在的巴雷特食管 (BO) 癌前状态驱动食管腺癌 (OAC) 的形成。
Oesophageal adenocarcinoma (OAC) is a deadly disease with poor survival statistics and few targeted therapies available. One of the most common molecular aberrations in OAC is amplification or activation of the gene encoding the receptor tyrosine kinase ERBB2, and ERBB2 is targeted in the clinic for this subset of patients. However, the downstream consequences of these ERBB2 activating events are not well understood. Here we used a combination of phosphoproteomics, open chromatin profiling and transcriptome analysis on cell line models and patient-derived datasets to interrogate the molecular pathways operating downstream from ERBB2. Integrated analysis of these data sets converge on a model where dysregulated ERBB2 signalling is mediated at the transcriptional level by the transcription factor AP-1. AP-1 in turn controls cell behaviour by acting on cohorts of genes that regulate cell migration and adhesion, features often associated with EMT. Our study therefore provides a valuable resource for the cancer cell signalling community and reveals novel molecular determinants underlying the dysregulated behaviour of OAC cells. Oncogenic ERBB2 signalling drives the formation of oesophageal adenocarcinoma (OAC) from the underlying Barrett's oesophagus (BO) precancerous state through activating the AP-1 transcription factor which in turn activates an EMT-like gene expression programme.