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

腫瘤基因療法說明

開會學習《腫瘤基因突變度與預防策略的實施計劃》《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 FAK 激活來協(xié)調(diào)乳腺癌向大腦轉(zhuǎn)移的進展》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。促進了腫瘤的正確治療與個性化用藥的發(fā)展，進一步強調(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)量迅速下降和預后不良為特征的嚴重疾病。臨床迫切需要開發(fā)有效的療法來預防和治療腦轉(zhuǎn)移。在這里，我們描述了一種獨特且穩(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腦轉(zhuǎn)移傳播和定植的分子機制。關(guān)鍵的實驗結(jié)果在額外的鼠 D2A1-BM2 模型和人類 MDA231-BrM2 模型中得到驗證。基因表達分析和功能研究，再加上臨床轉(zhuǎn)錄組學和組織病理學研究，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 促進同型腫瘤細胞粘附、異型腫瘤-星形膠質(zhì)細胞相互作用和 FAK 磷酸化。 FAK 信號促進 NF-κB 激活，誘導 Lamc2 表達和層粘連蛋白 332（層粘連蛋白 5）沉積、α6 整合素介導的粘附以及腦實質(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 抑制劑進行全身治療可減少腦轉(zhuǎn)移進展?？傊?，我們報告了乳腺癌腦轉(zhuǎn)移的自發(fā)模型，并確定 Cx 介導的 FAK-NF-κB 信號傳導是促進腦定植的細胞自主和微環(huán)境控制的細胞存活的機制。考慮到癌癥患者腦轉(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一步追求。

腫瘤發(fā)生與反復轉(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.

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