Nat Commun:科学家识别出驱动人类黑色素瘤发生的特定分子因素

2022-06-29 生物谷 生物谷

来自俄亥俄州立大学综合癌症中心等机构的科学家们通过研究发现了重要的分子信息,其或能帮助科学家们设计出针对难治性黑色素瘤的更有效的疗法和预防性策略。

近日,一篇发表在国际杂志Nature Communications上题为“Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation”的研究报告中,来自俄亥俄州立大学综合癌症中心等机构的科学家们通过研究发现了重要的分子信息,其或能帮助科学家们设计出针对难治性黑色素瘤的更有效的疗法和预防性策略。文章中,研究人员确定并描述了占15%-20%黑色素瘤的基因突变的关键特征。

图片来源:https://pubmed.ncbi.nlm.nih.gov/35672316/

利用一种临床前的实验模型,研究人员确定了在人类黑色素瘤中发生的特定NRAS基因突变的频率或与开启自发性黑色素瘤形成的基因突变的能力直接相关,这意味着,突变自身的特性(并非特定基因突变发生的难易程度)或许就是癌症形成的原因。NRAS突变的癌症非常难以治疗,因为目前并不存在免疫疗法以外的有效疗法,每一种癌症类型似乎都更偏爱特定“口味”的突变NRAS,但目前研究人员并不清楚其中的原因。

为此,研究人员想知道到底是什么样的机制能使得促进黑色素瘤的NRAS突变不同于促进其它癌症类型的突变,相关研究结果还能帮助研究人员确定黑色素瘤发生的早期事件并开发预防这类疾病的新型疗法。

为了进行这项研究,研究人员开发了一种遗传工程化的模型,其或能帮助他们激活黑色素瘤细胞(形成黑色素瘤的色素细胞)的9种不同的NRAS突变体中的一种。

令人惊讶的是,当研究人员激活仅在引发黑色素瘤发生的人类疾病中存在的这些基因突变时,他们发现,一些突变或许并不会引发黑色素瘤,而这些突变已知会引发白血病

相关研究结果表明,NRAS突变的选择对于每一种肿瘤类型都非常特殊,而且是癌症开始时发生的,而并不是像对诸如日光照射等特定的诱变事件产生反应。

文章中,研究人员确定了能够开启黑色素瘤的NRAS突变的外向结构的轻微变异,从而就会使得这些蛋白能与驱动黑色素瘤生长的信号通路发生相互作用。如今研究人员想通过研究靶向作用诱导黑色素瘤的NRAS突变的特定结构特征,从而来预防或治疗黑色素瘤。

本文研究结果证实了直到现在还是推测的一种观点,即RNS突变之间的微小差异或能确定哪种“口味”会导致特定的癌症,诸如此类概念或能用于寻找其它RAS驱动的肿瘤类型的弱点。

为了促进类似的研究发现,研究人员开发了8种新型且公开可用的遗传工程化修饰的小鼠模型,其或能作为整个RAS群体的必要工具包,这些模型或能用来激活并研究NRAS在其它相关癌症类型中的作用,比如结肠癌、白血病、骨髓瘤和甲状腺癌等,其还能用来地调查治疗这些疾病的新型药物。

研究人员所开发并用于这些研究的临床前研究模型或能提供给研究其它RAS驱动癌症类型的科学家,并帮其开发新型抗癌疗法。综上,本文研究为人类黑色素瘤特定NRAS突变的富集建立了一种机制性的基础。

原始出处:

Murphy, B.M., Terrell, E.M., Chirasani, V.R. et al. Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiationNat Commun 13, 3153 (2022).doi:10.1038/s41467-022-30881-9

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    2022-08-30 liye789132251
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    2022-07-24 liuli5079
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    2023-02-03 sunylz
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