Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells.
Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells.
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去势耐受性前列腺腔祖细胞的转录组学特征和生长因子调控。
DOI：
10.3390/cancers14153775
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发表时间：
2022-08-03
期刊：
影响因子：
5.2
通讯作者：
Goffin, Vincent
中科院分区：
文献类型：
--
作者：
Baures, Manon;Lombardi, Emilia Puig;Di Martino, Delphine;Zeitouni, Wail;Pacreau, Emeline;Dos Santos, Leila;Dariane, Charles;Boutillon, Florence;Guidotti, Jacques-Emmanuel;Goffin, Vincent
从去势敏感性前列腺癌到去势抵抗性前列腺癌（CRPC）的转变被假设是由前列腺腔细胞表现出去势耐受性、祖细胞和肿瘤引发能力驱动的。我们最近在CRPC相关小鼠模型中分离的LSCmed细胞符合这三个标准。使用各种生物信息学管道，我们在这里证明了LSCmed细胞与最近在人类前列腺和前列腺癌中发现的Club/Hillock细胞相匹配。我们确定EGFR/ERBB 4、IGF-1和MET通路是LSCmed细胞祖细胞和生长特性的关键调节因子。我们还证明，首次在去势耐受前列腺祖细胞的原代培养物中，这些生长因子途径的功能冗余赋予这些细胞绕过受体靶向药理学抑制的能力。鉴于CRPC患者中EGFR和MET靶向单药治疗的失败，我们的数据进一步支持LSCmed细胞作为研究驱动CRPC的细胞和分子机制的相关临床前模型。背景：去势抵抗性前列腺癌（CRPC）的分子和细胞机制仍然知之甚少。LSCmed细胞定义了一种FACS富集的去势耐受性管腔祖细胞群，已提出在Pten缺陷小鼠中促进肿瘤发生和CRPC。本研究的目的是通过分析LSCmed细胞与通过小鼠和人前列腺的单细胞（sc）RNA-seq分析鉴定的管腔祖细胞样细胞簇的分子接近性来评估LSCmed细胞的相关性，并研究其通过前列腺微环境中存在的计算机预测的生长因子的调节。方法：使用多个生物信息学管道进行泛转录组分析。使用RT-qPCR、免疫荧光和类器官测定表征通过细胞分选从健康和恶性小鼠前列腺分离的LSCmed细胞。结果如下：LSCmed细胞匹配（i）scRNA-seq分析中鉴定的小鼠管腔祖细胞簇，我们为其提供了共同的15个基因签名，包括先前鉴定的LSCmed标记物Krt 4，和（ii）人前列腺的Club/Hillock细胞。这种转录重叠在癌症背景下得以维持。EGFR/ERBB 4、IGF-1 R和MET通路被鉴定为LSCmed细胞的祖细胞、增殖和分化特性的自分泌/旁分泌调节剂。这些信号通路的功能冗余使它们能够绕过受体靶向药理学抑制剂的作用。结论：基于CRPC患者中对单一疗法失败的转录组学特征和药理学抗性，本研究支持LSCmed细胞作为研究去势耐受祖细胞在人前列腺癌进展中的作用的相关模型。
The shift from hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC) has been hypothesized to be driven by prostatic luminal cells exhibiting castration tolerance, progenitor and tumor-initiating capacity. LSCmed cells that we recently isolated in a relevant mouse model of CRPC fulfil these three criteria. Using various bioinformatic pipelines, we here demonstrate that LSCmed cells match Club/Hillock cells recently identified in human prostate and prostate cancer. We identified EGFR/ERBB4, IGF-1 and MET pathways as key regulators of LSCmed cell progenitor and growth properties. We also demonstrate, for the first time in primary cultures of castration-tolerant prostatic progenitor cells, that the functional redundancy of these growth factor pathways confers to these cells the ability to bypass receptor-targeted pharmacological inhibition. Given the failure of EGFR- and MET-targeted monotherapies in CRPC patients, our data further support LSCmed cells as a relevant preclinical model to study the cellular and molecular mechanisms driving CRPC. Background: The molecular and cellular mechanisms that drive castration-resistant prostate cancer (CRPC) remain poorly understood. LSCmed cells defines an FACS-enriched population of castration-tolerant luminal progenitor cells that has been proposed to promote tumorigenesis and CRPC in Pten-deficient mice. The goals of this study were to assess the relevance of LSCmed cells through the analysis of their molecular proximity with luminal progenitor-like cell clusters identified by single-cell (sc)RNA-seq analyses of mouse and human prostates, and to investigate their regulation by in silico-predicted growth factors present in the prostatic microenvironment. Methods: Several bioinformatic pipelines were used for pan-transcriptomic analyses. LSCmed cells isolated by cell sorting from healthy and malignant mouse prostates were characterized using RT-qPCR, immunofluorescence and organoid assays. Results: LSCmed cells match (i) mouse luminal progenitor cell clusters identified in scRNA-seq analyses for which we provide a common 15-gene signature including the previously identified LSCmed marker Krt4, and (ii) Club/Hillock cells of the human prostate. This transcriptional overlap was maintained in cancer contexts. EGFR/ERBB4, IGF-1R and MET pathways were identified as autocrine/paracrine regulators of progenitor, proliferation and differentiation properties of LSCmed cells. The functional redundancy of these signaling pathways allows them to bypass the effect of receptor-targeted pharmacological inhibitors. Conclusions: Based on transcriptomic profile and pharmacological resistance to monotherapies that failed in CRPC patients, this study supports LSCmed cells as a relevant model to investigate the role of castration-tolerant progenitor cells in human prostate cancer progression.
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单细胞转录组学鉴定远端前列腺内陷尖端中独特的管腔祖细胞类型
影响因子：
30.8
作者：
Guo W;Li L;He J;Liu Z;Han M;Li F;Xia X;Zhang X;Zhu Y;Wei Y;Li Y;Aji R;Dai H;Wei H;Li C;Chen Y;Chen L;Gao D
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64.5
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Chen Y
影响因子：
45.3
作者：
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Seymour, L
影响因子：
14.8
作者：
Drost J;Karthaus WR;Gao D;Driehuis E;Sawyers CL;Chen Y;Clevers H
通讯作者：
Clevers H
影响因子：
50.3
作者：
Carver BS;Chapinski C;Wongvipat J;Hieronymus H;Chen Y;Chandarlapaty S;Arora VK;Le C;Koutcher J;Scher H;Scardino PT;Rosen N;Sawyers CL
通讯作者：
Sawyers CL