PO.TB09.01 · 肿瘤生物学
单细胞转录组学在激素受体阳性乳腺癌中鉴定出具有侵袭性表型的EPCAM-low和EPCAM-negative上皮细胞群
Single-cell transcriptomics identifies distinct EPCAM-low and EPCAM-negative epithelial populations with aggressive phenotypes in hormone-receptor positive breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
激素受体阳性（HR+）乳腺癌的瘤内异质性尚未被完全阐明。本研究旨在对未经治疗的早期激素受体阳性（HR+）乳腺癌的上皮景观进行无偏倚的表征。我们对来自6例原发性HR+肿瘤的60,000余个未分选细胞进行了单细胞RNA测序。采用标准化的生物信息学流程进行聚类、差异基因表达和通路分析。关键发现通过多重免疫荧光和成像质谱流式细胞术（Imaging Mass Cytometry）进行空间验证。我们的无偏倚分析揭示了一个复杂的上皮景观。EPCAM-high细胞代表最大的腔上皮区室，具有高度异质性，聚类为多个患者特异性（"私有"）表型，这些表型强烈ER阳性，构成了每例患者独有的肿瘤指纹。相比之下，我们鉴定出两个不同的"公有"表型，存在于多例患者中，其EPCAM表达显著降低或缺失。第一个细胞群（EPCAM-low）表达一种独特的促炎特征，富集于干扰素-γ反应和KRAS信号通路。第二个细胞群（EPCAM-negative）与所有其他上皮细胞聚类距离较远，富集于侵袭性、干细胞样通路，包括经由NF-kB的TNF-alpha信号和Hedgehog信号。EPCAM-low/negative细胞群均为激素受体低表达。EPCAM-high区室是患者特异性细胞群的异质性混合体，而EPCAM-low/negative区室包含具有侵袭性、不可靶向表型的独特共享细胞群。这些发现揭示了一个预先存在的细胞储库，其可能驱动对内分泌治疗的原发性耐药，并促成晚期复发。本研究还强调，常见的基于标记物的上皮细胞分选方法可能无法捕捉HR+乳腺癌的完整异质性。
查看英文原文 English abstract
The intra-tumoral heterogeneity of hormone-receptor positive (HR+) breast cancers is incompletely known. The purpose of this study was to perform an unbiased characterization of the epithelial landscape in untreated, early-stage hormone-receptor positive (HR+) breast cancers. We performed single-cell RNA sequencing on over 60,000 unsorted cells from 6 primary HR+ tumors. A standardized bioinformatic pipeline was used for clustering, differential gene expression, and pathway analysis. Key findings were validated spatially using multiplexed immunofluorescence and Imaging Mass Cytometry. Our unbiased analysis revealed a complex epithelial landscape. The EPCAM-high cells, representing the largest luminal compartment, were highly heterogeneous and clustered into multiple patient-specific ("private") phenotypes that were strongly ER-positive and made up a tumor fingerprint unique to each patient. In contrast, we identified two distinct "public" phenotypes, present across multiple patients, with significantly reduced or absent EPCAM expression. The first population (EPCAM-low) expressed a unique pro-inflammatory signature enriched for interferon-gamma response and KRAS signaling pathways. The second population (EPCAM-negative) clustered distantly from all other epithelial cells and was enriched for aggressive, stem-like pathways, including TNF-alpha signaling via NF-kB and Hedgehog signaling. Both EPCAM-low/negative populations were hormone-receptor low. The EPCAM-high compartment is a heterogeneous mix of patient-specific populations, while the EPCAM-low/negative compartment contains distinct, shared populations with aggressive, non-targetable phenotypes. These findings reveal a pre-existing cellular reservoir that may drive de novo resistance to endocrine therapy and contribute to late recurrence. This work also highlights that common marker-based epithelial sorting methods may fail to capture the full heterogeneity of HR+ breast cancer.
利益披露 Disclosure
É. Di Lena, None..
A. Omeroglu, None.