Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA.
Department of Surgery and Oncology, Graduate School of Medicine, Kyushu University, Fukuoka, Japan.
Clin Transl Med. 2024 Jan;14(1):e1548. doi: 10.1002/ctm2.1548.
Intratumour heterogeneity is a hallmark of most solid tumours, including breast cancers. We applied spatial transcriptomics and single-cell RNA-sequencing on patient-derived xenografts (PDXs) to profile spatially resolved cell populations within oestrogen receptor-positive (ER ) breast cancer and to elucidate their importance in oestrogen-dependent tumour growth.
Two PDXs of 'ER-high' breast cancers with opposite oestrogen-mediated growth responses were investigated: oestrogen-suppressed GS3 (80-100% ER) and oestrogen-dependent SC31 (40-90% ER) models. The observation was validated via single-cell analyses on an 'ER-low' PDX, GS1 (5% ER). The results from our spatial and single-cell analyses were further supported by a public ER breast cancer single-cell dataset and protein-based dual immunohistochemistry (IHC) of SC31 examining important luminal cancer markers (i.e., ER, progesterone receptor and Ki67). The translational implication of our findings was assessed by clinical outcome analyses on publicly available cohorts.
Our space-gene-function study revealed four spatially distinct compartments within ER breast cancers. These compartments showed functional diversity (oestrogen-responsive, proliferative, hypoxia-induced and inflammation-related). The 'proliferative' population, rather than the 'oestrogen-responsive' compartment, was crucial for oestrogen-dependent tumour growth, leading to the acquisition of luminal B-like features. The cells expressing typical oestrogen-responsive genes like PGR were not directly linked to oestrogen-dependent proliferation. Dual IHC analyses demonstrated the distinct contribution of the Ki67 proliferative cells toward oestrogen-mediated growth and their response to a CDK4/6 inhibitor. The gene signatures derived from the proliferative, hypoxia-induced and inflammation-related compartments were significantly correlated with worse clinical outcomes, while patients with the oestrogen-responsive signature showed better prognoses, suggesting that this compartment would not be directly associated with oestrogen-dependent tumour progression.
Our study identified the gene signature in our 'proliferative' compartment as an important determinant of luminal cancer subtypes. This 'proliferative' cell population is a causative feature of luminal B breast cancer, contributing toward its aggressive behaviours.
肿瘤内异质性是大多数实体瘤（包括乳腺癌）的一个标志。我们应用空间转录组学和单细胞 RNA 测序对患者来源的异种移植（PDX）进行分析，以描绘雌激素受体阳性（ER ）乳腺癌中空间分辨的细胞群体，并阐明它们在雌激素依赖性肿瘤生长中的重要性。
研究了两种具有相反雌激素介导生长反应的“ER 高”乳腺癌 PDX：雌激素抑制的 GS3（80-100% ER）和雌激素依赖的 SC31（40-90% ER）模型。通过对“ER 低”PDX GS1（5% ER）的单细胞分析进行了验证。我们的空间和单细胞分析结果进一步得到了公共 ER 乳腺癌单细胞数据集和基于蛋白质的 SC31 双重免疫组织化学（IHC）的支持，该分析检查了重要的腔癌标志物（即 ER、孕激素受体和 Ki67）。通过对公开可用队列的临床结果分析评估了我们发现的转化意义。
我们的空间-基因-功能研究揭示了 ER 乳腺癌中四个空间上不同的隔室。这些隔室显示出功能多样性（雌激素反应性、增殖性、缺氧诱导和炎症相关）。对于雌激素依赖性肿瘤生长，“增殖性”群体而非“雌激素反应性”隔室至关重要，导致获得腔 B 样特征。表达典型雌激素反应性基因如 PGR 的细胞与雌激素依赖性增殖没有直接联系。双重 IHC 分析表明，Ki67 增殖细胞对雌激素介导的生长及其对 CDK4/6 抑制剂的反应具有明显的贡献。来自增殖、缺氧诱导和炎症相关隔室的基因特征与更差的临床结果显著相关，而具有雌激素反应性特征的患者具有更好的预后，这表明该隔室与雌激素依赖性肿瘤进展没有直接关系。
我们的研究确定了我们“增殖”隔室中的基因特征是腔癌亚型的重要决定因素。这种“增殖”细胞群是腔 B 乳腺癌的一个重要特征，导致其侵袭性行为。
