PO.TB07.01 · 肿瘤生物学
小鼠乳腺中异质性PROCR+细胞的单细胞多组学分析及其对乳腺癌的意义
Single cell multiomic profiling of heterogenousPROCR+ cells in mouse mammary gland and its implication for breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：乳腺是一个动态器官，在女性一生中经历广泛的组织重塑。在所有这些阶段，上皮的扩增均由位于层级顶端的成年乳腺上皮干细胞（MaSC）群体所支持。MaSC稳态需要在时间和空间上受到严格调控，以确保器官功能正常并避免病理后果。因此，干细胞活性的失调与肿瘤起始相关，而侵袭性乳腺癌常富集具有干细胞样特性的细胞。尽管MaSC对乳腺发育至关重要，但其确切身份和决定性特征仍知之甚少。值得注意的是，蛋白C受体（PROCR）标记了一小群具有干样特性的乳腺上皮细胞，但其丰度低阻碍了对它们的表征。
方法：在此，我们将靶向FACS富集与单细胞RNA测序及染色质可及性分析相结合，生成了跨发育阶段的PROCR⁺乳腺上皮细胞的多模态图谱。
结果概要：我们揭示了该区室内部的异质性，并鉴定出一个此前未被识别的Procr⁺、Cdh5⁻、Col1a1⁺群体，该群体表现出最高的发育潜能、最强的EMT样特征和最早的拟时序位置，与真正的乳腺干细胞（MaSC）状态一致。scRNA-seq与scATAC-seq的整合揭示了支配MaSC身份以及基底与腔上皮谱系定向的转录调控构架，包括其基序可及性和活性沿分化轨迹变化的直接主调控因子。与人乳腺上皮的比较分析鉴定出类似的PROCR⁺亚群，而对乳腺癌数据集的探究表明，Procr⁺、Cdh5⁻、Col1a1⁺的MaSC特征在三阴性和claudin-low肿瘤中选择性富集。
结论：这些发现完善了乳腺上皮的细胞层级结构，界定了支撑干性和谱系分叉的调控程序，并在一种独特的MaSC状态与侵袭性乳腺癌亚型的生物学之间建立了分子联系。
查看英文原文 English abstract
Introduction: The mammary gland is a dynamic organ that undergoes extensive tissue remodeling during the female lifetime. In all these stages, epithelial enlargement is supported by a population of adult mammary epithelial stem cells (MaSCs) residing at the apex of the hierarchy. MaSC homeostasis needs to be tightly regulated in time and space to ensure proper organ function and avoid pathological consequences. Thus, dysregulation of stem cell activity has been linked to tumor initiation, and aggressive breast cancers are frequently enriched in cells exhibiting stem cell like properties. Although MaSCs are fundamental to mammary gland development, their precise identity and defining characteristics remain poorly understood. Notably, protein C receptor (PROCR) marks a rare subset of mammary epithelial cells with stem-like properties, but their low abundance has hindered their characterization.
Methods: Here, we combine targeted FACS enrichment with single-cell RNA sequencing and chromatin accessibility profiling to generate a multimodal atlas of PROCR⁺ mammary epithelial cells across developmental stages.
Summary of results: We uncover heterogeneity within this compartment and identify a previously unrecognized Procr⁺, Cdh5⁻, Col1a1⁺ population that exhibits the highest developmental potency, strongest EMT-like signature, and earliest pseudotime position, consistent with a bona fide mammary stem cell (MaSC) state. Integration of scRNA-seq and scATAC-seq reveals the transcriptional regulatory architecture governing MaSC identity and basal versus luminal lineage commitment, including direct master regulators whose motif accessibility and activity shift along differentiation trajectories. Comparative analyses with human mammary epithelium identify analogous PROCR⁺ subpopulations, and interrogation of breast cancer datasets demonstrates that the Procr⁺, Cdh5⁻, Col1a1⁺ MaSC signature is selectively enriched in triple-negative and claudin-low tumors.
Conclusions: These findings refine the cellular hierarchy of the mammary epithelium, define regulatory programs underlying stemness and lineage bifurcation, and establish a molecular link between a distinct MaSC state and the biology of aggressive breast cancer subtypes.
利益披露 Disclosure
J. Silva, None..
K. Yan, None..
E. Nekritz, None.