The importance of fusion protein activity in Ewing sarcoma and the cell intrinsic and extrinsic factors that regulate it: A review.
The importance of fusion protein activity in Ewing sarcoma and the cell intrinsic and extrinsic factors that regulate it: A review.
复制标题
DOI：
10.3389/fonc.2022.1044707
复制
发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
越来越多的证据表明，尽管肿瘤起源于克隆，但最终会变成由表型不同的细胞亚群组成的复杂群体。这种异质性既源于肿瘤细胞的内在程序，也源于时空动态微环境的信号。虽然儿童癌症通常不像成人癌症那样具有大量突变，但它们仍然表现出高度的细胞异质性，且主要由表观遗传机制介导。尤因肉瘤是一种侵袭性的骨和软组织恶性肿瘤，在青春期发病率最高，复发和转移性疾病患者的预后很差。尤因肉瘤是由一种FET蛋白和一种ETS家族转录因子之间的特异性融合驱动的，其中最常见的是EWS::FLI1。尽管存在单一的驱动突变，但尤因肉瘤细胞在肿瘤之间和肿瘤内部都表现出高度的转录异质性。最近的研究已确定差异融合蛋白活性是这种异质性的一个关键来源，它导致了截然不同的细胞表型。矛盾的是，侵袭和转移潜能的增加与较低的EWS::FLI1活性有关。在此，我们综述了目前对EWS::FLI1活性、调节它的细胞自主性和肿瘤微环境因素以及这些活性状态对肿瘤进展的下游影响的了解。我们特别强调转录因子调节、信号通路调节以及细胞外基质是如何相互作用形成一个复杂的肿瘤细胞表型网络的。我们提出，阐明这些关键要素相互作用的机制将有助于开发新的治疗方法，这些方法旨在针对这种复杂性并最终改善患者的治疗效果。
Accumulating evidence shows that despite clonal origins tumors eventually become complex communities comprised of phenotypically distinct cell subpopulations. This heterogeneity arises from both tumor cell intrinsic programs and signals from spatially and temporally dynamic microenvironments. While pediatric cancers usually lack the mutational burden of adult cancers, they still exhibit high levels of cellular heterogeneity that are largely mediated by epigenetic mechanisms. Ewing sarcomas are aggressive bone and soft tissue malignancies with peak incidence in adolescence and the prognosis for patients with relapsed and metastatic disease is dismal. Ewing sarcomas are driven by a single pathognomonic fusion between a FET protein and an ETS family transcription factor, the most common of which is EWS::FLI1. Despite sharing a single driver mutation, Ewing sarcoma cells demonstrate a high degree of transcriptional heterogeneity both between and within tumors. Recent studies have identified differential fusion protein activity as a key source of this heterogeneity which leads to profoundly different cellular phenotypes. Paradoxically, increased invasive and metastatic potential is associated with lower EWS::FLI1 activity. Here, we review what is currently understood about EWS::FLI1 activity, the cell autonomous and tumor microenvironmental factors that regulate it, and the downstream consequences of these activity states on tumor progression. We specifically highlight how transcription factor regulation, signaling pathway modulation, and the extracellular matrix intersect to create a complex network of tumor cell phenotypes. We propose that elucidation of the mechanisms by which these essential elements interact will enable the development of novel therapeutic approaches that are designed to target this complexity and ultimately improve patient outcomes.
登录
查看更多内容
影响因子：
6.2
作者：
Applebaum, Mark A.;Worch, Jennifer;Matthay, Katherine K.;Goldsby, Robert;Neuhaus, John;West, Daniel C.;DuBois, Steven G.
通讯作者：
DuBois, Steven G.
影响因子：
3.8
作者：
Knowles HJ;Schaefer KL;Dirksen U;Athanasou NA
通讯作者：
Athanasou NA
影响因子：
5.2
作者：
通讯作者：
--
影响因子：
4.7
作者：
Barrett C;Budhiraja A;Parashar V;Batish M
通讯作者：
Batish M
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF