【佳學基因檢測】BAF 染色質重塑劑的結構破壞通過恢復侵襲性表觀基因組程序損害神經母細胞瘤轉移

靶向藥一個月費用排序

閱讀聽到《Mol Cancer》在.?2022 Sep 3;21(1):175.發(fā)表了一篇題目為《BAF 染色質重塑劑的結構破壞通過恢復侵襲性表觀基因組程序損害神經母細胞瘤轉移》腫瘤靶向藥物治療基因檢測臨床研究文章。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。促進了腫瘤的正確治療與個性化用藥的發(fā)展，進一步強調了基因信息檢測與分析的重要性。

腫瘤靶向藥物及正確治療臨床研究內容關鍵詞：

癌癥,染色質重塑,表觀遺傳學,表觀基因組學,轉移,成神經細胞瘤, SWI/SNF

腫瘤靶向治療基因檢測臨床應用結果

背景：發(fā)育過程中的表觀遺傳編程對于確定細胞譜系至關重要，而這種編程的改變有助于胚胎腫瘤發(fā)育的開始。在神經母細胞瘤中，神經嵴祖細胞阻斷其自然分化為交感腎上腺素能細胞的過程，導致侵襲性和轉移性兒科癌癥的發(fā)展。研究負責致癌表觀基因組網絡的表觀遺傳調節(jié)因子對于開發(fā)針對這些腫瘤的基于表觀遺傳的新療法至關重要。哺乳動物開關/蔗糖非發(fā)酵 (mSWI/SNF) ATP 依賴性染色質重塑復合物在全基因組范圍內發(fā)揮作用，將表觀遺傳信號轉化為開放染色質狀態(tài)。本研究旨在了解 mSWI/SNF 對神經母細胞瘤致癌表觀基因組的貢獻及其作為治療靶點的潛力。方法：使用蛋白質組學方法在神經母細胞瘤細胞中進行 mSWI/SNF 復合物的功能表征，功能喪失實驗、轉錄組和染色質可及性分析，以及體外和體內測定。結果：神經母細胞瘤細胞包含三種主要的 mSWI/SNF 亞型，但只有通過沉默其關鍵結構亞基 ARID1A 和 ARID1B 來破壞 BRG1 相關因子 (BAF) 復合物，通過促進細胞周期阻斷來損害細胞增殖。全基因組染色質重塑和轉錄組分析表明，BAF 破壞導致涉及整合素、鈣粘蛋白和關鍵間充質調節(jié)劑的廣泛侵襲性相關表達程序的表觀遺傳抑制，從而減少對細胞外基質的粘附和隨后的體外侵襲，并顯著降低抑制體內神經母細胞瘤轉移的起始和生長。結論：我們報告了 BAF 復合物在維持允許神經母細胞瘤侵襲和轉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 藥理學結構破壞物用于治療開發(fā)在轉移性神經母細胞瘤中。關鍵詞：癌癥；染色質重塑；表觀遺傳學；表觀基因組學；轉移;成神經細胞瘤; SWI/SNF。

腫瘤發(fā)生與反復轉移國際數據庫描述：

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.