Toward understanding cancer stem cell heterogeneity in the tumor microenvironment
Toward understanding cancer stem cell heterogeneity in the tumor microenvironment
复制标题
了解肿瘤微环境中的癌症干细胞异质性
DOI：
10.1073/pnas.1815345116
复制
发表时间：
2019-01-02
影响因子：
11.1
通讯作者：
Jolly, Mohit Kumar
中科院分区：
文献类型：
--
作者：
Bocci, Federico;Gearhart-Serna, Larisa;Jolly, Mohit Kumar
上皮间质转化（EMT）和癌症干细胞（CSC）形成是驱动肿瘤进展、治疗耐药和癌症转移的两个重要过程。最近的实验表明，具有不同 EMT 和 CSC 表型的细胞在原发肿瘤中存在空间分离。然而，在肿瘤微环境中产生这种时空动态的潜在机制在很大程度上仍未被探索。在这里，我们通过基于机制的动力学模型表明，EMT 诱导信号（如 TGF-β）的扩散，加上通过 Notch 信号通路对 EMT 和 CSC 决策进行非细胞自主控制，可以解释实验观察到的肿瘤中具有不同 EMT 表型的 CSC 子集的不同定位。我们的模拟显示，更多的间充质 CSC 位于侵袭边缘，而混合上皮/间充质 (E/M) CSC 则位于肿瘤内部。此外，受 Notch-Jagged 信号传导在介导 EMT 和 Sternness 中的作用的启发，我们研究了促进 Notch-Jagged 信号传导的微环境因素。我们表明，许多炎症细胞因子（例如 IL-6）可以促进 Notch-Jagged 信号传导，可以（i）稳定混合 E/M 表型，（ii）增加混合 E/M 细胞空间邻近的可能性，以及（iii）扩大 CSC 的比例。为了验证Notch-Jagged信号传导与sternness之间的预测联系，我们在体外敲低了杂交E/M SUM149人乳腺癌细胞中的JAG1。 JAG1 敲低显着限制了肿瘤类器官的形成，证实了 Notch-Jagged 信号在肿瘤进展中发挥的关键作用。我们的综合计算实验框架共同揭示了 EMT 和 CSC 时空动力学的基本原理。
The epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation are two paramount processes driving tumor progression, therapy resistance, and cancer metastasis. Recent experiments show that cells with varying EMT and CSC phenotypes are spatially segregated in the primary tumor. The underlying mechanisms generating such spatiotemporal dynamics in the tumor microenvironment, however, remain largely unexplored. Here, we show through a mechanism-based dynamical model that the diffusion of EMT-inducing signals such as TGF-beta, together with noncell autonomous control of EMT and CSC decision making via the Notch signaling pathway, can explain experimentally observed disparate localization of subsets of CSCs with varying EMT phenotypes in the tumor. Our simulations show that the more mesenchymal CSCs lie at the invasive edge, while the hybrid epithelial/mesenchymal (E/M) CSCs reside in the tumor interior. Further, motivated by the role of Notch-Jagged signaling in mediating EMT and sternness, we investigated the microenvironmental factors that promote Notch-Jagged signaling. We show that many inflammatory cytokines such as IL-6 that can promote Notch-Jagged signaling can (i) stabilize a hybrid E/M phenotype, (ii) increase the likelihood of spatial proximity of hybrid E/M cells, and (iii) expand the fraction of CSCs. To validate the predicted connection between Notch-Jagged signaling and sternness, we knocked down JAG1 in hybrid E/M SUM149 human breast cancer cells in vitro. JAG1 knockdown significantly restricted tumor organoid formation, confirming the key role that Notch-Jagged signaling can play in tumor progression. Together, our integrated computational-experimental framework reveals the underlying principles of spatiotemporal dynamics of EMT and CSCs.