Transcriptome Analysis of Individual Stromal Cell Populations Identifies Stroma-Tumor Crosstalk in Mouse Lung Cancer Model
Transcriptome Analysis of Individual Stromal Cell Populations Identifies Stroma-Tumor Crosstalk in Mouse Lung Cancer Model
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DOI：
10.1016/j.celrep.2015.01.040
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发表时间：
2015-02-24
期刊：
影响因子：
8.8
通讯作者：
Mittal, Vivek
中科院分区：
文献类型：
--
作者：
Choi, Hyejin;Sheng, Jianting;Mittal, Vivek
新出现的研究已经开始证明，重新编程的基质细胞在肿瘤的生长、转移和耐药中发挥着关键作用。然而，间质细胞在非小细胞肺癌(NSCLC)中的作用仍未被充分研究。我们使用Kras基因驱动的NSCLC原位模型系统地分析了特定的造血基质细胞在肺癌中的作用。对单独分选的髓系细胞和肿瘤上皮细胞的RNA深度测序分析揭示了特定细胞类型的差异调节基因，表明基质激活。我们开发了一个基于配体-受体相互作用和下游信号网络的串扰信号发现计算模型，并在非小细胞肺癌中发现了已知和新的肿瘤间质旁分泌和肿瘤自分泌串扰信号通路。我们提供对肺癌微环境成分的细胞和分子洞察，这些成分有助于癌症的发生。这项研究有可能开发针对肿瘤-间质相互作用的治疗策略，并可能补充传统的抗癌治疗。
Emerging studies have begun to demonstrate that reprogrammed stromal cells play pivotal roles in tumor growth, metastasis, and resistance to therapy. However, the contribution of stromal cells to non-smallcell lung cancer (NSCLC) has remained underexplored. We used an orthotopic model of Kras-driven NSCLC to systematically dissect the contribution of specific hematopoietic stromal cells in lung cancer. RNA deep-sequencing analysis of individually sorted myeloid lineage and tumor epithelial cells revealed cell-type-specific differentially regulated genes, indicative of activated stroma. We developed a computational model for crosstalk signaling discovery based on ligand-receptor interactions and downstream signaling networks and identified known and novel tumor-stroma paracrine and tumor autocrine crosstalk-signaling pathways in NSCLC. We provide cellular and molecular insights into components of the lung cancer microenvironment that contribute to carcinogenesis. This study has the potential for development of therapeutic strategies that target tumor-stroma interactions and maycomplement conventional anti-cancer treatments.