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The PAX-FOXO1s trigger fast trans-differentiation of chick embryonic neural cells into alveolar rhabdomyosarcoma with tissue invasive properties limited by S phase entry inhibition
PLOS Genetics ( IF 4.0 ) Pub Date : 2020-11-11 , DOI: 10.1371/journal.pgen.1009164
Gloria Gonzalez Curto 1 , Audrey Der Vartanian 2 , Youcef El-Mokhtar Frarma 1 , Line Manceau 1 , Lorenzo Baldi 1 , Selene Prisco 1 , Nabila Elarouci 3 , Frédéric Causeret 4, 5 , Daniil Korenkov 1 , Muriel Rigolet 2 , Frédéric Aurade 2, 6 , Aurélien De Reynies 3 , Vincent Contremoulins 7 , Frédéric Relaix 2 , Orestis Faklaris 7 , James Briscoe 8 , Pascale Gilardi-Hebenstreit 1 , Vanessa Ribes 1
Affiliation  

The chromosome translocations generating PAX3-FOXO1 and PAX7-FOXO1 chimeric proteins are the primary hallmarks of the paediatric fusion-positive alveolar subtype of Rhabdomyosarcoma (FP-RMS). Despite the ability of these transcription factors to remodel chromatin landscapes and promote the expression of tumour driver genes, they only inefficiently promote malignant transformation in vivo. The reason for this is unclear. To address this, we developed an in ovo model to follow the response of spinal cord progenitors to PAX-FOXO1s. Our data demonstrate that PAX-FOXO1s, but not wild-type PAX3 or PAX7, trigger the trans-differentiation of neural cells into FP-RMS-like cells with myogenic characteristics. In parallel, PAX-FOXO1s remodel the neural pseudo-stratified epithelium into a cohesive mesenchyme capable of tissue invasion. Surprisingly, expression of PAX-FOXO1s, similar to wild-type PAX3/7, reduce the levels of CDK-CYCLIN activity and increase the fraction of cells in G1. Introduction of CYCLIN D1 or MYCN overcomes this PAX-FOXO1-mediated cell cycle inhibition and promotes tumour growth. Together, our findings reveal a mechanism that can explain the apparent limited oncogenicity of PAX-FOXO1 fusion transcription factors. They are also consistent with certain clinical reports indicative of a neural origin of FP-RMS.



中文翻译:


PAX-FOXO1触发鸡胚神经细胞快速转分化为肺泡横纹肌肉瘤,其组织侵袭特性受到S期进入抑制的限制



产生 PAX3-FOXO1 和 PAX7-FOXO1 嵌合蛋白的染色体易位是儿童横纹肌肉瘤融合阳性肺泡亚型 (FP-RMS) 的主要标志。尽管这些转录因子能够重塑染色质景观并促进肿瘤驱动基因的表达,但它们只能低效地促进体内恶性转化。其原因尚不清楚。为了解决这个问题,我们开发了一个卵内模型来追踪脊髓祖细胞对 PAX-FOXO1 的反应。我们的数据表明,PAX-FOXO1(而非野生型 PAX3 或 PAX7)触发神经细胞转分化为具有生肌特征的 FP-RMS 样细胞。与此同时,PAX-FOXO1 将神经假复层上皮重塑为能够侵袭组织的粘性间质。令人惊讶的是,与野生型 PAX3/7 类似,PAX-FOXO1 的表达降低了 CDK-CYCLIN 活性水平并增加了 G1 期细胞的比例。 CYCLIN D1 或 MYCN 的引入克服了 PAX-FOXO1 介导的细胞周期抑制并促进肿瘤生长。总之,我们的研究结果揭示了一种机制,可以解释 PAX-FOXO1 融合转录因子明显有限的致癌性。它们也与某些表明 FP-RMS 神经起源的临床报告一致。

更新日期:2020-11-12
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