Gastrointestinal stromal tumours (GISTs), the most common mesenchymal neoplasm of the gastrointestinal tract, result from deregulated proliferation of transformed KIT‐positive interstitial cells of Cajal that share mesenchymal progenitors with smooth muscle cells. Despite the identification of selective KIT inhibitors, primary resistance and relapse remain a major concern. Moreover, most patients develop resistance partly through reactivation of KIT and its downstream signalling pathways. We previously identified the Limb Expression 1 (LIX1 ) gene as a unique marker of digestive mesenchyme immaturity. We also demonstrated that LIX1 regulates mesenchymal progenitor proliferation and differentiation by controlling the Hippo effector YAP1, which is constitutively activated in many sarcomas. Therefore, we wanted to determine LIX1 role in GIST development. We found that LIX1 is strongly up‐regulated in GIST samples and this is associated with unfavourable prognosis. Moreover, LIX1 controls GIST cell proliferation in vitro and in vivo. Upon LIX1 inactivation in GIST cells, YAP1/TAZ activity is reduced, KIT (the GIST signature) is down‐regulated, and cells acquire smooth muscle lineage features. Our data highlight LIX1 role in digestive mesenchyme‐derived cell‐fate decisions and identify this novel regulator as a target for drug design for GIST treatment by influencing its differentiation status.

中文翻译：

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LIX1 调节 YAP 活性并控制胃肠道癌细胞的可塑性。

胃肠道间质瘤 (GIST) 是胃肠道最常见的间充质肿瘤，是由与平滑肌细胞共享间充质祖细胞的 Cajal 转化 KIT 阳性间质细胞增殖失调引起的。尽管确定了选择性 KIT 抑制剂，但原发耐药和复发仍然是一个主要问题。此外，大多数患者部分通过重新激活 KIT 及其下游信号通路产生耐药性。我们之前确定了肢体表达 1 ( LIX1) 基因作为消化间充质不成熟的独特标记。我们还证明 LIX1 通过控制 Hippo 效应子 YAP1 来调节间充质祖细胞的增殖和分化，YAP1 在许多肉瘤中被组成性激活。因此，我们想确定 LIX1 在 GIST 开发中的作用。我们发现 LIX1 在 GIST 样本中强烈上调，这与不利的预后有关。此外，LIX1 在体外和体内控制 GIST 细胞增殖。在LIX1 上GIST 细胞失活，YAP1/TAZ 活性降低，KIT（GIST 特征）下调，细胞获得平滑肌谱系特征。我们的数据突出了 LIX1 在消化间充质衍生细胞命运决定中的作用，并通过影响其分化状态将这种新型调节剂确定为 GIST 治疗药物设计的靶点。