小柯机器人

美国加州大学尔湾分校Kai Kessenbrock团队发现，癌前基质细胞促进BRCA1介导的乳腺肿瘤发生。相关论文于2023年3月13日在线发表在《自然—遗传学》杂志上。

研究人员表明，恶性前的基质微环境促进了上皮细胞的增殖和突变体BRCA1驱动的肿瘤发生。使用单细胞RNA测序分析人类癌前BRCA1^+/mut和非携带者的乳腺组织，研究人员发现了上皮细胞稳态的不同变化，包括基底层中间祖细胞的增殖和扩张。此外，BRCA1^+/mut基质细胞显示出促增殖旁分泌信号的表达增加。更为重要的是，研究人员发现癌前相关的成纤维细胞（pre-CAF）产生促增殖因子，包括基质金属蛋白酶3（MMP3），它在体内促进BRCA1驱动的肿瘤发生。总之，这些研究结果表明，BRCA1^+/mut的癌前基质可能通过促进上皮细胞的增殖和分化改变的腔内祖细胞的积累而提高乳腺癌风险。

据介绍，患有种系BRCA1突变（BRCA1^+/mut）的妇女患遗传性乳腺癌的风险增加。BRCA1^+/mut的癌症启动与乳腺上皮的恶性肿瘤前期变化有关；然而，在BRCA1驱动的肿瘤启动过程中，与上皮相关基质微环境的作用仍不清楚。

附：英文原文

Title: Preneoplastic stromal cells promote BRCA1-mediated breast tumorigenesis

Author: Nee, Kevin, Ma, Dennis, Nguyen, Quy H., Pein, Maren, Pervolarakis, Nicholas, Insua-Rodrguez, Jacob, Gong, Yanwen, Hernandez, Grace, Alshetaiwi, Hamad, Williams, Justice, Rauf, Maha, Dave, Kushal Rajiv, Boyapati, Keerti, Hasnain, Aliza, Calderon, Christian, Markaryan, Anush, Edwards, Robert, Lin, Erin, Parajuli, Ritesh, Zhou, Peijie, Nie, Qing, Shalabi, Sundus, LaBarge, Mark A., Kessenbrock, Kai

Issue&Volume: 2023-03-13

Abstract: Women with germline BRCA1 mutations (BRCA1+/mut) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1+/mut is associated with premalignant changes in breast epithelium; however, the role of the epithelium-associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here we show that the premalignant stromal niche promotes epithelial proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell RNA sequencing analysis of human preneoplastic BRCA1+/mut and noncarrier breast tissues, we show distinct changes in epithelial homeostasis including increased proliferation and expansion of basal-luminal intermediate progenitor cells. Additionally, BRCA1+/mut stromal cells show increased expression of pro-proliferative paracrine signals. In particular, we identify pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven tumorigenesis in vivo. Together, our findings demonstrate that precancerous stroma in BRCA1+/mut may elevate breast cancer risk through the promotion of epithelial proliferation and an accumulation of luminal progenitor cells with altered differentiation.

DOI: 10.1038/s41588-023-01298-x

Source: https://www.nature.com/articles/s41588-023-01298-x

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex