【佳學(xué)基因檢測】連接蛋白通過促進(jìn) FAK 激活來協(xié)調(diào)乳腺癌向大腦轉(zhuǎn)移的進(jìn)展

腫瘤基因療法說明

開會學(xué)習(xí)《腫瘤基因突變度與預(yù)防策略的實(shí)施計(jì)劃》《Sci Transl Med》在.?2022 Sep 7;14(661):eaax8933.發(fā)表了一篇題目為《連接蛋白通過促進(jìn) FAK 激活來協(xié)調(diào)乳腺癌向大腦轉(zhuǎn)移的進(jìn)展》腫瘤靶向藥物治療基因檢測臨床研究文章。該研究由Girieca Lorusso,?Christof B Wyss,?Fran?ois Kuonen,?Nicola Vannini,?Clotilde Billottet,?Nathalie Duffey,?Raphael Pineau,?Qiang Lan,?Pratyaksha Wirapati,?David Barras,?Alessandro Tancredi,?Ruth Lyck,?Hans-Anton Lehr,?Britta Engelhardt,?Mauro Delorenzi,?Andreas Bikfalvi,?Curzio Rüegg?等完成。促進(jìn)了腫瘤的正確治療與個性化用藥的發(fā)展，進(jìn)一步強(qiáng)調(diào)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(nèi)容關(guān)鍵詞：

腫瘤靶向治療基因檢測臨床應(yīng)用結(jié)果

腦轉(zhuǎn)移是晚期乳腺癌患者發(fā)病率增加的并發(fā)癥。這是一種以生活質(zhì)量迅速下降和預(yù)后不良為特征的嚴(yán)重疾病。臨床迫切需要開發(fā)有效的療法來預(yù)防和治療腦轉(zhuǎn)移。在這里，我們描述了一種獨(dú)特且穩(wěn)健的小鼠乳腺癌腦轉(zhuǎn)移 (4T1-BM2) 自發(fā)臨床前模型，該模型有助于揭示指導(dǎo)腦轉(zhuǎn)移傳播和定植的分子機(jī)制。關(guān)鍵的實(shí)驗(yàn)結(jié)果在額外的鼠 D2A1-BM2 模型和人類 MDA231-BrM2 模型中得到驗(yàn)證?；虮磉_(dá)分析和功能研究，再加上臨床轉(zhuǎn)錄組學(xué)和組織病理學(xué)研究，將連接蛋白 (Cxs) 和粘著斑激酶 (FAK) 確定為協(xié)調(diào)大腦乳腺癌定植的主要分子。 Cx31 促進(jìn)同型腫瘤細(xì)胞粘附、異型腫瘤-星形膠質(zhì)細(xì)胞相互作用和 FAK 磷酸化。 FAK 信號促進(jìn) NF-κB 激活，誘導(dǎo) Lamc2 表達(dá)和層粘連蛋白 332（層粘連蛋白 5）沉積、α6 整合素介導(dǎo)的粘附以及腦實(shí)質(zhì)內(nèi)的持續(xù)存活和生長。在 MDA231-BrM2 模型中，人類同源分子 CX43、LAMA4 和 α3 整合素參與其中。用 FAK 抑制劑進(jìn)行全身治療可減少腦轉(zhuǎn)移進(jìn)展?？傊覀儓?bào)告了乳腺癌腦轉(zhuǎn)移的自發(fā)模型，并確定 Cx 介導(dǎo)的 FAK-NF-κB 信號傳導(dǎo)是促進(jìn)腦定植的細(xì)胞自主和微環(huán)境控制的細(xì)胞存活的機(jī)制?？紤]到癌癥患者腦轉(zhuǎn)移性疾病的治療選擇有限，我們建議將 FAK 作為治療候選者在臨床上進(jìn)一步追求。

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

Brain metastasis is a complication of increasing incidence in patients with breast cancer at advanced disease stage. It is a severe condition characterized by a rapid decline in quality of life and poor prognosis. There is a critical clinical need to develop effective therapies to prevent and treat brain metastases. Here, we describe a unique and robust spontaneous preclinical model of breast cancer metastasis to the brain (4T1-BM2) in mice that has been instrumental in uncovering molecular mechanisms guiding metastatic dissemination and colonization of the brain. Key experimental findings were validated in the additional murine D2A1-BM2?model and in human MDA231-BrM2?model. Gene expression analyses and functional studies, coupled with clinical transcriptomic and histopathological investigations, identified connexins (Cxs) and focal adhesion kinase (FAK) as master molecules orchestrating breast cancer colonization of the brain. Cx31 promoted homotypic tumor cell adhesion, heterotypic tumor-astrocyte interaction, and FAK phosphorylation. FAK signaling prompted NF-κB activation inducing Lamc2 expression and laminin 332 (laminin 5) deposition, α6 integrin-mediated adhesion, and sustained survival and growth within brain parenchyma. In the MDA231-BrM2?model, the human homologous molecules CX43, LAMA4, and α3 integrin were involved. Systemic treatment with FAK inhibitors reduced brain metastasis progression. In conclusion, we report a spontaneous model of breast cancer metastasis to the brain and identified Cx-mediated FAK-NF-κB signaling as a mechanism promoting cell-autonomous and microenvironmentally controlled cell survival for brain colonization. Considering the limited therapeutic options for brain metastatic disease in cancer patients, we propose FAK as a therapeutic candidate to further pursue in the clinic.