Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells
Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells
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DOI：
10.1073/pnas.1618298114
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发表时间：
2017-03-21
影响因子：
11.1
通讯作者：
Weinberg, Robert A.
中科院分区：
文献类型：
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作者：
Bierie, Brian;Pierce, Sarah E.;Weinberg, Robert A.
个体癌内的肿瘤细胞通常在其上皮细胞与间充质样细胞状态中表现出相当大的表型异质性。由于具有间充质特征的癌细胞通常对治疗更具抗性，并且可能成为复发的来源，因此我们试图确定这些细胞是否可以进一步分层为功能不同的亚型。事实上，我们发现基底上皮标志物整合素-β 4（ITGB 4）可用于使间充质样三阴性乳腺癌（TNBC）细胞分层，所述细胞在其相对致瘤能力方面彼此不同。值得注意的是，我们证明了ITGB 4（+）癌症干细胞（CSC）富集的间充质细胞处于中间上皮/间充质表型状态。在接受化疗的TNBC患者中，ITGB 4表达升高与5年无复发生存率降低相关。从机制上讲，我们发现高度间充质SUM 159 TNBC细胞中的ZEB 1（锌指E-box binding homeobox 1）转录因子活性可以抑制上皮转录因子TAp 63 alpha（肿瘤蛋白63同种型1）的表达，TAp 63 alpha是一种促进ITGB 4表达的蛋白质。此外，我们证明了ZEB 1和ITGB 4在调节源自间充质TNBC细胞的肿瘤的组织病理学表型中是重要的。因此，间充质癌细胞群体在内部是异质的，并且ITGB 4是一种机制驱动的预后生物标志物，可用于鉴定TNBC中更具侵袭性的间充质癌细胞亚型。快速分离和机械地询问CSC富集的部分间充质癌细胞的能力应进一步使得能够鉴定新的治疗机会以改善患有TNBC的高风险患者的预后。
Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin-beta 4 (ITGB4), can be used to enable stratification of mesenchymal like triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4(+) cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival. Mechanistically, we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63 alpha (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC.