Identification and characterization of a proliferative cell population in estrogen receptor-positive metastatic breast cancer through spatial and single-cell transcriptomics
Identification and characterization of a proliferative cell population in estrogen receptor-positive metastatic breast cancer through spatial and single-cell transcriptomics
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通过空间和单细胞转录组学鉴定和表征雌激素受体阳性转移性乳腺癌中的增殖细胞群
DOI：
10.1101/2023.01.31.526403
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Chen Shiuan
中科院分区：
文献类型：
--
作者：
Yoshitake Ryohei;Mori Hitomi;Ha Desiree;Wu Xiwei;Wang Jinhui;Wang Xiaoqiang;Saeki Kohei;Chang Gregory;Shim Hyun Jeong;Chan Yin;Chen Shiuan
肿瘤异质性是大多数实体肿瘤的一个特征，包括乳腺癌。我们应用空间转录组学和单细胞rna测序技术来分析雌激素受体阳性（ER+）转移性乳腺癌的空间分解细胞群，并阐明它们在雌激素依赖性肿瘤生长中的重要性。方法对两种具有相反雌激素介导生长反应的“ER高”转移性乳腺癌患者来源的异种移植物（PDXs）进行空间转录组学和单细胞rna测序：雌激素抑制的GS3 （80-100% ER）和雌激素刺激的SC31 （30-75% ER）模型。分析包括用和不用17β-雌二醇处理的样品。研究结果通过“低ER”雌激素加速PDX， GS1 （5% ER）的scRNA-seq分析得到验证。我们的空间分析和单细胞分析结果进一步得到了公开的单细胞数据集分析和基于蛋白质的双免疫组化（IHC）评估的支持，该评估使用了三个重要的临床标志物[即ER，孕激素受体（PR）和Ki67]。通过对公共乳腺癌队列的临床结果分析评估了这些结果的翻译意义。我们的新空间基因功能研究揭示了在ER+转移性乳腺癌中除了三个主要的空间不同的区室外，还有一个“增殖”细胞群。这些隔室显示出功能多样性（即雌激素反应性、增殖性、缺氧诱导和炎症相关）。“增殖性（MKI67+）”细胞群，而非“雌激素响应性”细胞室，对雌激素依赖性肿瘤生长至关重要，导致获得腔内B特征。诱导典型的雌激素应答基因（如aspgr1）的细胞与雌激素依赖性增殖没有直接联系。此外，双IHC分析表明，Ki67+增殖细胞对雌激素介导的生长和它们对palbociclib（一种CDK4/6抑制剂）的反应有明显的贡献。增殖性、低氧诱导和炎症相关的基因特征与较差的临床结果显著相关，而雌激素反应评分高的患者预后较好，证实了雌激素反应性隔间与雌激素依赖性肿瘤进展没有直接关系。结论我们的研究首次阐明了在ER+转移性乳腺癌中明显分布的“增殖”细胞群。它们对这些癌症的进展有不同的贡献，“增殖”室中的基因特征是腔内癌症亚型的重要决定因素。
BackgroundIntratumor heterogeneity is a hallmark of most solid tumors, including breast cancers. We applied spatial transcriptomics and single-cell RNA-sequencing technologies to profile spatially resolved cell populations within estrogen receptor-positive (ER+) metastatic breast cancers and elucidate their importance in estrogen-dependent tumor growth.MethodsSpatial transcriptomics and single-cell RNA-sequencing were performed on two patient-derived xenografts (PDXs) of “ER-high” metastatic breast cancers with opposite estrogen-mediated growth responses: estrogen-suppressed GS3 (80–100% ER) and estrogen-stimulated SC31 (30–75% ER) models. The analyses included samples treated with and without 17β-estradiol. The findings were validated via scRNA-seq analyses on “ER-low” estrogen-accelerating PDX, GS1 (5% ER). The results from our spatial and single-cell analyses were further supported by the analysis of a publicly available single cell dataset and a protein-based dual immunohistochemical (IHC) evaluation using three important clinical markers [i.e., ER, progesterone receptor (PR), and Ki67]. The translational implication of these results was assessed by clinical outcome analyses on public breast cancer cohorts.ResultsOur novel space-gene-function study revealed a “proliferative” cell population in addition to three major spatially distinct compartments within ER+metastatic breast cancers. These compartments showed functional diversity (i.e., estrogen-responsive, proliferative, hypoxia-induced, and inflammation-related). The “proliferative (MKI67+)” population, not “estrogen-responsive” compartment, was crucial for estrogen-dependent tumor growth, leading to the acquisition of luminal B features. The cells with induction of typical estrogen-responsive genes such asPGRwere not directly linked to estrogen-dependent proliferation. Additionally, the dual IHC analyses demonstrated the distinct contribution of the Ki67+proliferative cells toward estrogen-mediated growth and their response to palbociclib, a CDK4/6 inhibitor. The gene signatures developed from the proliferative, hypoxia-induced, and inflammation-related compartments were significantly correlated with worse clinical outcomes, while patients with the high estrogen-responsive scores showed better prognosis, confirming that the estrogen-responsive compartment would not be directly associated with estrogen-dependent tumor progression.ConclusionsFor the first time, our study elucidated a “proliferative” cell population distinctly distributed in ER+metastatic breast cancers. They contribute differently toward progression of these cancers, and the gene signature in the “proliferative” compartment is an important determinant of luminal cancer subtypes.
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影响因子：
16.6
作者：
通讯作者：
--
影响因子：
3.9
作者：
Wang Y;Tzeng YT;Chang G;Wang X;Chen S
通讯作者：
Chen S
DOI：
10.1073/pnas.1115188108
发表时间：
2011-11-22
影响因子：
11.1
作者：
Ariazi, Eric A.;Cunliffe, Heather E.;Jordan, V. Craig
通讯作者：
Jordan, V. Craig
整合单细胞蛋白质组学和转录组学的人类乳房图集。
影响因子：
11.8
作者：
Gray, G. Kenneth;Li, Carman Man-Chung;Rosenbluth, Jennifer M.;Selfors, Laura M.;Girnius, Nomeda;Lin, Jia-Ren;Schackmann, Ron C. J.;Goh, Walter L.;Moore, Kaitlin;Shapiro, Hana K.;Mei, Shaolin;D'Andrea, Kurt;Nathanson, Katherine L.;Sorger, Peter K.;Santagata, Sandro;Regev, Aviv;Garber, Judy E.;Dillon, Deborah A.;Brugge, Joan S.
通讯作者：
Brugge, Joan S.
影响因子：
28.2
作者：
Cerami E;Gao J;Dogrusoz U;Gross BE;Sumer SO;Aksoy BA;Jacobsen A;Byrne CJ;Heuer ML;Larsson E;Antipin Y;Reva B;Goldberg AP;Sander C;Schultz N
通讯作者：
Schultz N