【佳學(xué)基因檢測(cè)】BAF 染色質(zhì)重塑劑的結(jié)構(gòu)破壞通過恢復(fù)侵襲性表觀基因組程序損害神經(jīng)母細(xì)胞瘤轉(zhuǎn)移

靶向藥一個(gè)月費(fèi)用排序

閱讀聽到《Mol Cancer》在.?2022 Sep 3;21(1):175.發(fā)表了一篇題目為《BAF 染色質(zhì)重塑劑的結(jié)構(gòu)破壞通過恢復(fù)侵襲性表觀基因組程序損害神經(jīng)母細(xì)胞瘤轉(zhuǎn)移》腫瘤靶向藥物治療基因檢測(cè)臨床研究文章。該研究由Carlos Jiménez,?Roberta Antonelli,?Mariona Nadal-Ribelles,?Laura Devis-Jauregui,?Pablo Latorre,?Carme Solé,?Marc Masanas,?Adrià Molero-Valenzuela,?Aroa Soriano,?Josep Sánchez de Toledo,?David Llobet-Navas,?Josep Roma,?Francesc Posas,?Eulàlia de Nadal,?Soledad Gallego,?Lucas Moreno,?Miguel F Segura?等完成。促進(jìn)了腫瘤的正確治療與個(gè)性化用藥的發(fā)展，進(jìn)一步強(qiáng)調(diào)了基因信息檢測(cè)與分析的重要性。

腫瘤靶向藥物及正確治療臨床研究?jī)?nèi)容關(guān)鍵詞：

癌癥,染色質(zhì)重塑,表觀遺傳學(xué),表觀基因組學(xué),轉(zhuǎn)移,成神經(jīng)細(xì)胞瘤, SWI/SNF

腫瘤靶向治療基因檢測(cè)臨床應(yīng)用結(jié)果

背景：發(fā)育過程中的表觀遺傳編程對(duì)于確定細(xì)胞譜系至關(guān)重要，而這種編程的改變有助于胚胎腫瘤發(fā)育的開始。在神經(jīng)母細(xì)胞瘤中，神經(jīng)嵴祖細(xì)胞阻斷其自然分化為交感腎上腺素能細(xì)胞的過程，導(dǎo)致侵襲性和轉(zhuǎn)移性兒科癌癥的發(fā)展。研究負(fù)責(zé)致癌表觀基因組網(wǎng)絡(luò)的表觀遺傳調(diào)節(jié)因子對(duì)于開發(fā)針對(duì)這些腫瘤的基于表觀遺傳的新療法至關(guān)重要。哺乳動(dòng)物開關(guān)/蔗糖非發(fā)酵 (mSWI/SNF) ATP 依賴性染色質(zhì)重塑復(fù)合物在全基因組范圍內(nèi)發(fā)揮作用，將表觀遺傳信號(hào)轉(zhuǎn)化為開放染色質(zhì)狀態(tài)。本研究旨在了解 mSWI/SNF 對(duì)神經(jīng)母細(xì)胞瘤致癌表觀基因組的貢獻(xiàn)及其作為治療靶點(diǎn)的潛力。方法：使用蛋白質(zhì)組學(xué)方法在神經(jīng)母細(xì)胞瘤細(xì)胞中進(jìn)行 mSWI/SNF 復(fù)合物的功能表征，功能喪失實(shí)驗(yàn)、轉(zhuǎn)錄組和染色質(zhì)可及性分析，以及體外和體內(nèi)測(cè)定。結(jié)果：神經(jīng)母細(xì)胞瘤細(xì)胞包含三種主要的 mSWI/SNF 亞型，但只有通過沉默其關(guān)鍵結(jié)構(gòu)亞基 ARID1A 和 ARID1B 來破壞 BRG1 相關(guān)因子 (BAF) 復(fù)合物，通過促進(jìn)細(xì)胞周期阻斷來損害細(xì)胞增殖。全基因組染色質(zhì)重塑和轉(zhuǎn)錄組分析表明，BAF 破壞導(dǎo)致涉及整合素、鈣粘蛋白和關(guān)鍵間充質(zhì)調(diào)節(jié)劑的廣泛侵襲性相關(guān)表達(dá)程序的表觀遺傳抑制，從而減少對(duì)細(xì)胞外基質(zhì)的粘附和隨后的體外侵襲，并顯著降低抑制體內(nèi)神經(jīng)母細(xì)胞瘤轉(zhuǎn)移的起始和生長(zhǎng)。結(jié)論：我們報(bào)告了 BAF 復(fù)合物在維持允許神經(jīng)母細(xì)胞瘤侵襲和轉(zhuǎn)移的表觀基因組程序中的新的 ATP 酶非依賴性作用，敦促開發(fā)新的 BAF 藥理學(xué)結(jié)構(gòu)破壞物用于治療開發(fā)在轉(zhuǎn)移性神經(jīng)母細(xì)胞瘤中。關(guān)鍵詞：癌癥；染色質(zhì)重塑；表觀遺傳學(xué)；表觀基因組學(xué)；轉(zhuǎn)移;成神經(jīng)細(xì)胞瘤; SWI/SNF。

腫瘤發(fā)生與反復(fù)轉(zhuǎn)移國(guó)際數(shù)據(jù)庫描述：

Background:?Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target.Methods:?Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays.Results:?Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo.Conclusions:?We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma.Keywords:?Cancer; Chromatin remodelling; Epigenetics; Epigenomics; Metastasis; Neuroblastoma; SWI/SNF.

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