IT之家 4 月 4 日消息，復(fù)旦大學(xué)附屬腫瘤醫(yī)院今日宣布，該院院長虞先濬教授團隊聯(lián)合北京大學(xué)腫瘤醫(yī)院、中國科學(xué)院上海藥物研究所、上海長海醫(yī)院、中國科學(xué)院分子細胞科學(xué)卓越創(chuàng)新中心，歷時五年完成全球首個無功能性胰腺神經(jīng)內(nèi)分泌瘤（NF-pNET）多組學(xué)全景圖譜研究。
國際頂級腫瘤學(xué)期刊《癌細胞》（Cancer Cell）今日發(fā)表該項重要研究成果，影響因子為 48.8 分。
研究團隊不但繪制出了全球首張無功能性胰腺神經(jīng)內(nèi)分泌瘤多組學(xué)全景圖譜，還根據(jù)圖譜突破性提出這種“沉默腫瘤”的分子分型框架、預(yù)后模型和靶向-免疫治療新策略，為臨床精準診療提供了重要依據(jù)。
IT之家注：胰腺神經(jīng)內(nèi)分泌瘤是發(fā)生在胰腺的第二大常見腫瘤，約 90% 為無功能性。這類無功能性胰腺神經(jīng)內(nèi)分泌瘤早期沒有癥狀，因而也被稱作“沉默的腫瘤”。
針對此類難題，虞先濬教授團隊聯(lián)合多中心研究團隊，整合基因組、轉(zhuǎn)錄組、蛋白質(zhì)組和磷酸化修飾組四種組學(xué)數(shù)據(jù)，對 108 例中國患者樣本進行多維分析，繪制出全景分子圖譜，揭示了 MEN1、ATRX、DAXX 基因突變通過干擾染色質(zhì)結(jié)構(gòu)穩(wěn)定性和激活 mTOR 通路驅(qū)動腫瘤惡性演進的機制。
研究團隊還通過 MEN1 基因條件性敲除小鼠模型，驗證了 MEN1 缺失觸發(fā)代謝重編程和增殖信號交叉激活的惡性循環(huán)，從而導(dǎo)致染色體分離至關(guān)重要的 CENPV 蛋白下調(diào)，填補了該領(lǐng)域機制研究的空白。另外，CDK5、WASL 等基因的拷貝數(shù)擴增被發(fā)現(xiàn)為無功能性胰腺神經(jīng)內(nèi)分泌瘤生長的驅(qū)動因素，有望成為靶向治療的潛在“靶標(biāo)”。
為了解決這一臨床困境，研究團隊基于海量蛋白質(zhì)組數(shù)據(jù)，利用前期研發(fā)的 ReProMSig平臺基于人工智能算法篩選出 GNAO1、INA、VCAN 三個蛋白質(zhì)，構(gòu)建的預(yù)后模型在 345 例患者驗證中顯示出顯著區(qū)分度 —— 高危組五年生存率 51.4%，低危組達 97.8%。更具突破性的是，血漿 VCAN 濃度檢測有望替代組織活檢實現(xiàn)無創(chuàng)監(jiān)測。
研究團隊進一步通過蛋白質(zhì)組學(xué)特征聚類分析，將無功能性胰腺神經(jīng)內(nèi)分泌瘤患者劃分為四種分子亞型，為臨床治療提供了“按圖索驥”的精準路線。
其中 C1 亞型的腫瘤以免疫抑制微環(huán)境和 EMT 通路激活為特征，患者預(yù)后最差，急需探索免疫聯(lián)合療法；C2亞型表現(xiàn)出異?；钴S的氧化磷酸化活性；C3 亞型由 MYC異常激活和失控的細胞周期信號主導(dǎo)；C4亞型則在 VHL 突變驅(qū)動下形成獨特的缺氧生態(tài)。
研究團隊后續(xù)的藥物研究證實了“四分型”的準確性。基于各亞型特異激活的蛋白激酶和表達 / 活性上調(diào)蛋白，團隊利用患者來源類器官（PDO）開展了藥物篩選并利用患者來源腫瘤異種移植模型（PDX）進行驗證，證實 CDK5 抑制劑可抑制四種分子亞型的腫瘤生長；鈣離子通道阻滯劑（如心血管疾病經(jīng)典藥物鹽酸胺碘酮）與CDK5抑制劑兩藥聯(lián)用在 C2 亞型中表現(xiàn)出更好的抑瘤效果；目前臨床運用的 mTOR抑制劑可較好抑制 C4亞型腫瘤。這些證據(jù)顯示，基于“四分型”的“分型而治”策略，為個體化精準治療提供了科學(xué)依據(jù)。http://m.share.gzmuoj.com/f7q/detail/e9c
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虞先濬教授表示，該研究是國際上首次大規(guī)模對胰腺神經(jīng)內(nèi)分泌瘤臨床隊列開展的多組學(xué)綜合分析，研究成果為無功能性的胰腺神經(jīng)內(nèi)分泌瘤的發(fā)病機制解析、預(yù)后預(yù)測、分子分型及個體化治療提供了堅實的理論依據(jù)，有望推動胰腺神經(jīng)內(nèi)分泌瘤研究領(lǐng)域的快速發(fā)展。
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