单细胞测序探索三阴性乳腺癌治未病
中国最早的医学典籍《黄帝内经》早在两千多年前就指出：圣人不治已病治未病。不过，早期发现癌症的主要障碍之一是我们对肿瘤启动事件了解不足。历来，癌症研究一直集中于已发生肿瘤的组织学和分子学特征，从而发现了数百种假设的驱动突变。目前尚不清楚肿瘤启动细胞的这些基因突变如何影响新生肿瘤细胞状态及其微环境。例如，乳腺癌易感基因BRCA1是重要的抑癌基因，如果发生致病突变和功能丧失，容易引起乳腺癌等恶性肿瘤。已知BRCA1所致三阴性乳腺癌来源于乳腺管腔原始细胞，但是目前尚不明确BRCA1功能丧失和伴随突变如何影响乳腺管腔原始细胞状态及其微环境并最终导致恶变。
2021年3月9日，英国《自然》旗下《自然通讯》在线发表英国癌症研究中心、剑桥大学、曼彻斯特大学、惠康基金会桑格研究所、欧洲生物信息研究所的研究报告，探讨了如何在三阴性乳腺癌形成之前，按时间窗对基因工程小鼠乳腺肿瘤模型进行单细胞基因转录核糖核酸（RNA）测序，以解决上述难题。
该研究发现，干扰乳腺管腔原始细胞BRCA1和基因组守护者p53，可诱发乳腺泡状细胞异常的癌前分化，并伴随免疫微环境发生促进肿瘤形成的变化。与妊娠期间乳腺泡状细胞分化不同的是，该过程为细胞自发，其特征为驱动乳腺泡状细胞生成的转录因子失调。
因此，该研究结果表明，BRCA1和p53的功能丧失意外促进了管腔原始细胞癌前分化过程，突显了原始细胞决定作用，并为BRCA1肿瘤组织特异性阐明了潜在机制，为三阴性乳腺癌治未病奠定了基础。
Nat Commun. 2021 Mar 9;12(1):1502.
Time-resolved single-cell analysis of BRCA1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors.
Karsten Bach, Sara Pensa, Marija Zarocsinceva, Katarzyna Kania, Julie Stockis, Silvain Pinaud, Kyren A. Lazarus, Mona Shehata, Bruno M. Simoes, Alice R. Greenhalgh, Sacha J. Howell, Robert B. Clarke, Carlos Caldas, Timotheus Y. F. Halim, John C. Marioni, Walid T. Khaled.
University of Cambridge, Cambridge, UK; Cancer Research UK, Cambridge Cancer Centre, Cambridge, UK; Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK; University of Manchester, Manchester, UK; Christie NHS Foundation Trust, Manchester, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK; European Bioinformatics Institute, Hinxton, UK.
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.
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.
DOI: 10.1038/s41467-021-21783-3