研究建立乳腺癌驅(qū)動因素鑒定新方法
美國弗雷德·哈欽森癌癥研究中心Slobodan Beronja研究團隊揭示等位乳腺祖細胞的胚胎條形碼在功能上可確定乳腺癌的驅(qū)動因素。相關(guān)論文在線發(fā)表在2020年2月13日的《細胞—干細胞》上。
研究人員表示，羊膜內(nèi)慢病毒注射可以有效地轉(zhuǎn)導成年乳腺的祖細胞，并以此為平臺對500多個遺傳性病變進行功能篩選，以了解其在腫瘤形成中的作用。靶向祖細胞在成年動物中建立了管腔和肌上皮細胞系的長期克隆，并且通過使用穩(wěn)定條形碼的譜系追蹤。研究發(fā)現(xiàn)每只小鼠的乳腺都是由一定數(shù)量的大約120個早期祖細胞產(chǎn)生的，這些祖細胞具有一致地均等生長擴增潛力。然后，他們設(shè)計了一個體內(nèi)篩選來測試乳腺癌中的遺傳相互作用，確定了不僅能促進腫瘤形成也能驅(qū)動分子亞型產(chǎn)生的候選物。因此，該方法使得能夠在乳腺上皮中快速且高通量地發(fā)現(xiàn)癌癥驅(qū)動因素。
據(jù)了解，在完整的乳腺上皮中識別乳腺癌的臨床相關(guān)驅(qū)動因素對于理解腫瘤發(fā)生至關(guān)重要，但事實證明這仍具有挑戰(zhàn)性。
附：英文原文
Title: Embryonic Barcoding of Equipotent Mammary Progenitors Functionally Identifies Breast Cancer Drivers
Author: Zhe Ying, Slobodan Beronja
Issue&Volume: February 13, 2020
Abstract: Identification of clinically relevant drivers of breast cancers in intact mammaryepithelium is critical for understanding tumorigenesis yet has proven challenging.Here, we show that intra-amniotic lentiviral injection can efficiently transduce progenitorcells of the adult mammary gland and use that as a platform to functionally screenover 500 genetic lesions for functional roles in tumor formation. Targeted progenitorsestablish long-term clones of both luminal and myoepithelial lineages in adult animals,and via lineage tracing with stable barcodes, we found that each mouse mammary glandis generated from a defined number of ～120 early progenitor cells that expand uniformlywith equal growth potential. We then designed an in vivo screen to test genetic interactions in breast cancer and identified candidates thatdrove not only tumor formation but also molecular subtypes. Thus, this methodologyenables rapid and high-throughput cancer driver discovery in mammary epithelium.
DOI: 10.1016/j.stem.2020.01.009
Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30009-6
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