Landragin Camille, Saichi Melissa, Laisné Marthe, Durand Adeline, Prompsy Pacôme, Leclere Renaud, Mesple Jérémy, Borgman Kyra, Trouchet Amandine, Faraldo Marisa M, Chiche Aurélie, Vincent-Salomon Anne, Salmon Hélène, Vallot Céline
Institut Curie, CNRS UMR3244, PSL University, Paris, France.
Translational Research Department, Institut Curie, PSL University, Paris, France.
Mol Cancer. 2025 Apr 28;24(1):127. doi: 10.1186/s12943-025-02331-9.
In breast cancer related to the BRCA1 mutation, luminal progenitor cells are believed to be the cells of origin, yet how these cells transform into invasive cancer cells remain poorly understood. Here, we combine single-cell epigenomic and transcriptomic data to reconstitute sequences of events in luminal cells that lead to tumorigenesis. Upon deletion of Trp53 and Brca1, we find that luminal progenitors display an extensive epigenomic disorder associated with a loss of cell identity. These cells then progress to tumor formation through a partial epithelial-to-mesenchymal transition, orchestrated by Snail and the timely activation of immunosuppressive and FGF signaling with their microenvironment. In human samples, pre-tumoral changes can be detected in early stage, basal-like tumors, which rarely recur, as well as in normal-like mammary glands of BRCA1 mutation carriers who have had cancer. Our study fills critical gaps in our understanding of BRCA1-driven tumorigenesis, opening perspectives for the early monitoring of individuals with high cancer risk.
在与BRCA1突变相关的乳腺癌中，管腔祖细胞被认为是起源细胞，但这些细胞如何转变为浸润性癌细胞仍知之甚少。在这里，我们结合单细胞表观基因组和转录组数据，以重构管腔细胞中导致肿瘤发生的事件序列。在缺失Trp53和Brca1后，我们发现管腔祖细胞表现出与细胞身份丧失相关的广泛表观基因组紊乱。这些细胞随后通过部分上皮-间质转化发展为肿瘤，这一过程由Snail以及它们与微环境中免疫抑制和FGF信号的及时激活所协调。在人类样本中，在早期的基底样肿瘤（很少复发）以及患过癌症的BRCA1突变携带者的类正常乳腺中都可以检测到肿瘤前变化。我们的研究填补了我们对BRCA1驱动的肿瘤发生理解中的关键空白，为早期监测高癌症风险个体开辟了前景。
