Vimentin Is Required for Lung Adenocarcinoma Metastasis via Heterotypic Tumor Cell-Cancer-Associated Fibroblast Interactions during Collective Invasion.
Vimentin Is Required for Lung Adenocarcinoma Metastasis via Heterotypic Tumor Cell-Cancer-Associated Fibroblast Interactions during Collective Invasion.
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波形蛋白是肺腺癌在集体侵袭过程中通过异型肿瘤细胞-癌症相关成纤维细胞相互作用进行转移所必需的。
DOI：
10.1158/1078-0432.ccr-17-1776
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发表时间：
2018-01-15
期刊：
影响因子：
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通讯作者：
Marcus AI
中科院分区：
文献类型：
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作者：
Richardson AM;Havel LS;Koyen AE;Konen JM;Shupe J;Wiles WG 4th;Martin WD;Grossniklaus HE;Sica G;Gilbert-Ross M;Marcus AI
Vimentin是一种上皮细胞向间质转化（EMT）的生物标志物和中间丝蛋白，在细胞迁移过程中起维持细胞结构和运动的作用。尽管大量的临床数据表明vimentin与患者预后不良有关，但尚不清楚vimentin是转移所必需的还是相关的生物标志物。我们建立了一种新的基因工程小鼠模型（GEMM）来探测波形蛋白在肺腺癌转移中的作用。我们使用了LSL-KrasG12D/Lkb1fl/fl/Vim - / -模型（KLV - / -），该模型包含了vimentin的全身敲除，来源于cre依赖性的LSL-KrasG12D/Lkb1fl/fl模型（KLV+/+）。我们比较了GEMMs的转移表型，并分析了KLV模型和肺腺癌患者的原发肿瘤，以评估vimentin的表达和功能。KLV+/+和KLV - / -小鼠的特征表明，虽然肺原发肿瘤生长不需要波形蛋白，但转移需要波形蛋白，波形蛋白缺失会导致低级别原发性肿瘤。有趣的是，在KLV+/+小鼠中，vimentin在肿瘤细胞中不表达，但在上皮肿瘤细胞集体侵袭包（CIPs）周围的癌症相关成纤维细胞（CAFs）中表达，KLV−/−小鼠的CIPs显著减少。cip与肿瘤分级相关，并且是vimentin阴性和e -cadherin阳性，表明缺乏癌细胞EMT。在人肺腺癌样本中也观察到类似的异型染色模式。体外研究表明，CAF运动导致肿瘤细胞侵袭需要弧度蛋白，支持弧度蛋白依赖的集体侵袭模型。这些数据表明，在集体侵袭过程中，通过维持异型肿瘤细胞- caf相互作用，波形蛋白是肺腺癌转移所必需的。
Vimentin is an epithelial to mesenchymal transition (EMT) biomarker and intermediate filament protein that functions during cell migration to maintain structure and motility. Despite the abundance of clinical data linking vimentin to poor patient outcome, it is unclear if vimentin is required for metastasis or is a correlative biomarker. We developed a novel genetically engineered mouse model (GEMM) to probe vimentin in lung adenocarcinoma metastasis. We used the LSL-KrasG12D/Lkb1fl/fl/Vim−/− model (KLV−/−), which incorporates a whole-body knockout of vimentin and is derived from the Cre-dependent LSL-KrasG12D/Lkb1fl/fl model (KLV+/+). We compared the metastatic phenotypes of the GEMMs and analyzed primary tumors from the KLV models and lung adenocarcinoma patients to assess vimentin expression and function. Characterization of KLV+/+ and KLV−/− mice, show that while vimentin is not required for primary lung tumor growth, vimentin is required for metastasis and vimentin loss generates lower grade primary tumors. Interestingly, in the KLV+/+ mice, vimentin was not expressed in tumor cells but in cancer-associated fibroblasts (CAFs) surrounding collective invasion packs (CIPs) of epithelial tumor cells, with significantly less CIPs in KLV−/− mice. CIPs correlate with tumor grade, and are vimentin-negative and E-cadherin-positive, indicating a lack of cancer cell EMT. A similar heterotypic staining pattern was observed in human lung adenocarcinoma samples. In vitro studies show that vimentin is required for CAF motility to lead tumor cell invasion, supporting a vimentin-dependent model of collective invasion. These data show that vimentin is required for lung adenocarcinoma metastasis by maintaining heterotypic tumor cell-CAF interactions during collective invasion.