PO.TB10.01 · 肿瘤生物学
基质细胞cyclin D1通过转录调控E结构域促进前列腺癌干性
Stromal cyclin D1 promotes prostate cancer stemness via the transcriptional regulatory E domain
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
• 引言。前列腺癌"干性"随肿瘤进展而增加，预示不良预后，并促成治疗耐药。cyclin D1基因（CCND1）编码一种全酶的调节亚基，该全酶可磷酸化RB并传递转录特性，其在前列腺癌中表达并增强某些去势抵抗性前列腺癌的生长。临床试验正在前列腺癌中靶向cyclin D1的激酶活性。cyclin D1 E结构域的功能意义仍有待进一步明确。我们研究了cyclin D1在前列腺癌中潜在的不依赖激酶的功能。• 方法。分析患者基因表达、肿瘤组织学、基因敲除转基因小鼠、组织培养干细胞实验、蛋白质组学分析。• 发现。我们显示，与相邻组织相比，cyclin D1在前列腺癌（PCa）肿瘤基质中表达增加。使用单细胞测序，我们在癌相关成纤维细胞中鉴定出cyclin D1。在体内，PCa干性的细胞标志物包括Trop2 ICD活性。同时删除上皮细胞和基质细胞的cyclin D1进一步降低了PCa干细胞标志物，提示上皮外基质细胞cyclin D1在诱导PCa干性中的作用。在体外，用cyclin D1回补cyclin D1缺陷的成纤维细胞表明，cyclin D1调控一种分泌组，可增强前列腺癌干性（通过前列腺癌球体大小和数量以及促干性趋化因子受体（CXCR2、CX3CR1）的表达来评估）。突变分析显示，cyclin D1对干性和趋化因子受体表达的异型诱导需要cyclin D1羧基末端内一个本质无序的富酸性"E结构域"（氨基酸272-280）。整合蛋白质组学和ChIP-Seq鉴定出调控癌症干性和促肿瘤炎症的转录靶点。• 结论。cyclin D1通过一个本质无序的羧基末端结构域，经异型功能增强前列腺癌干性。
查看英文原文 English abstract
• Introduction. Prostate cancer “stemness” increases with tumor progression, predicts poor prognosis and contributes to therapy resistance. The cyclin D1 gene (CCND1), which encodes the regulatory subunit of a holoenzyme that phosphorylates RB and conveys transcriptional properties, is expressed in prostate cancer and augments growth of some castrate resistant prostate cancers. Clinical trials are targeting the kinase activity of cyclin D1 in prostate cancer. The functional significance of the cyclin D1 E domain remained to be further defined. We investigated a potential kinase-independent function of cyclin D1 in prostate cancer. • Methods . Analysis of patient gene expression, tumor histology, gene knockout transgenic mice, tissue culture stem cell assays, proteomic analysis. • Findings . We show cyclin D1 expression is increased in PCa tumor stroma compared with adjacent tissue. Using single cell sequencing cyclin D1 we identified cyclin D1 in cancer associated fibroblasts. In vivo, cell markers of PCa stemness including Trop2 ICD activity. Deletion of both epithelial cell and stromal cyclin D1 further reduced markers of PCa stem cells suggesting a role for extra epithelial stromal cell cyclin D1 in the induction of PCa stemness. In vitro, cyclin D1 rescue of cyclin D1 deficient fibroblasts demonstrated cyclin D1 governed a secretome that augmented prostate cancer stemness, assessed by prostate cancer sphere size and number, and expression of pro-stemness chemokine receptors (CXCR2, CX3CR1). Mutational analysis showed the cyclin D1 heterotypic induction of stemness and chemokine receptor expression required an intrinsically disordered acidic rich “E domain” (AA 272-280) within the cyclin D1 carboxyl terminus. Integrated proteomics and ChIP Seq identified transcriptional targets governing cancer stemness and pro-tumorigenic inflammation. • Conclusions. Cyclin D1 augments prostate cancer stemness through heterotypic functions via an intrinsically disordered carboxyl terminal domain.
利益披露 Disclosure
X. Jiao,
StromaGenesis LLC ).
LightSeed LLC ).
EcoGenome LLC ).
CytoDyn Inc ).
D. Li,
Stromagenesis LLC ).
Cytodyn Inc ).
Ecogenome LLC ).
R. Pancsa, None.
R. Harish,
Stromagensis LLC ).
Cytodyn Inc ).
Lightseed LLC ).
Ecogenome LLC ).
Z. Li,
StromaGenesis LLC ).
Ecogenome LLC ).
Lightseed ).
Cytodyn Inc ).
G. Tolufashe, None.
H. Rui,
IHG Biosciences Independent Contractor.
Y. Du, None..
H. Tang, None..
P. Tompa, None.
R. G. Pestell,
Cytodyn Inc Stock, ), Travel, Consultant, Warrants.
StromaGenesis LLC Stock, Travel, Patent, CEO and owner.
EcoGenome LLC. Stock, Travel, Patent, CEO and owner.
LightSeed LLC Stock, Travel, Patent, CEO and owner.
Shenandoah Pharmaceuticals LLC Stock, Travel, Patent, CEO and owner.
ioROC Therapeutics LLC Stock, Travel, Patent, CEO and owner.
HUN-REN National Advisory Board (Hungary) Consultant, Payment or honoraria for lectures.
National Cancer Institute NCI Cancer Center Reviewer – Subcommittee A.