Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors.
Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors.
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DOI：
10.1038/s41467-021-21783-3
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发表时间：
2021-03-09
影响因子：
16.6
通讯作者：
Khaled WT
中科院分区：
文献类型：
--
作者：
Bach K;Pensa S;Zarocsinceva M;Kania K;Stockis J;Pinaud S;Lazarus KA;Shehata M;Simões BM;Greenhalgh AR;Howell SJ;Clarke RB;Caldas C;Halim TYF;Marioni JC;Khaled WT
目前尚不清楚遗传畸变如何影响新生肿瘤细胞及其微环境的状态。BRCA 1驱动的三阴性乳腺癌（TNBC）已被证明是由管腔祖细胞引起的，但对BRCA 1功能丧失（LOF）和伴随的突变如何影响管腔祖细胞状态知之甚少。在这里，我们展示了如何在肿瘤形成之前对基因工程小鼠模型进行时间分辨的单细胞分析，以应对这一挑战。我们发现，扰动腔祖细胞中的Brca 1/p53诱导异常肺泡分化癌前伴随着促肿瘤发生的免疫室的变化。与妊娠期间的肺泡分化不同，该过程是细胞自主的，其特征在于驱动肺泡发生的转录因子的失调。基于我们的数据，我们提出了一个模型，其中Brca 1/p53 LOF无意中促进了管腔祖细胞中的分化程序，突出了起源细胞的确定性作用，并为BRCA 1肿瘤的组织特异性提供了一个潜在的解释。BRCA 1驱动的乳腺癌起源于管腔祖细胞，但BRCA 1功能丧失如何影响疾病癌前阶段的管腔祖细胞状态仍不清楚。在这里，作者证明了管腔祖细胞向部分分泌管腔细胞表型的异常分化，这种分化发生在肿瘤起始的早期阶段的Brca 1缺陷型乳腺癌小鼠模型和来自BRCA 1携带者的乳腺细胞中。
It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours. BRCA1 driven breast cancer arises from luminal progenitor cells but how BRCA1 loss-of-function affects the luminal progenitor cell state during premalignant stages of the disease is still unclear. Here, the authors demonstrate an aberrant differentiation of luminal progenitors towards a partial secretory luminal cell phenotype that occurs in a Brca1 deficient mouse model of breast cancer at early stages of tumour initiation and in breast cells from BRCA1 carriers.
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影响因子：
14.9
作者：
Lun AT;Smyth GK
通讯作者：
Smyth GK
影响因子：
12.3
作者：
Lun AT;Bach K;Marioni JC
通讯作者：
Marioni JC
影响因子：
56.9
作者：
Poole, Aleksandra Jovanovic;Li, Ying;Lee, Eva Y. -H. P.
通讯作者：
Lee, Eva Y. -H. P.
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
14.8
作者：
Efremova, Mirjana;Vento-Tormo, Miquel;Vento-Tormo, Roser
通讯作者：
Vento-Tormo, Roser