Vimentin Is Required for Lung Adenocarcinoma Metastasis via Heterotypic Tumor Cell-Cancer-Associated Fibroblast Interactions during Collective Invasion.

Autor:	Richardson AM; Cancer Biology Graduate Program, Emory University, Atlanta, Georgia.; Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia.; Winship Cancer Institute of Emory University, Atlanta, Georgia., Havel LS; Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia.; Winship Cancer Institute of Emory University, Atlanta, Georgia., Koyen AE; Cancer Biology Graduate Program, Emory University, Atlanta, Georgia.; Winship Cancer Institute of Emory University, Atlanta, Georgia.; Department of Radiation Oncology, Emory University, Atlanta, Georgia., Konen JM; Cancer Biology Graduate Program, Emory University, Atlanta, Georgia.; Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia.; Winship Cancer Institute of Emory University, Atlanta, Georgia., Shupe J; Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia.; Winship Cancer Institute of Emory University, Atlanta, Georgia., Wiles WG 4th; Winship Cancer Institute of Emory University, Atlanta, Georgia.; The Cancer Animal Models Shared Resource., Martin WD; Winship Cancer Institute of Emory University, Atlanta, Georgia.; The Cancer Animal Models Shared Resource., Grossniklaus HE; Winship Cancer Institute of Emory University, Atlanta, Georgia.; Department of Ophthalmology, Emory University, Atlanta, Georgia., Sica G; Winship Cancer Institute of Emory University, Atlanta, Georgia.; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia., Gilbert-Ross M; Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia. aimarcu@emory.edu mmgilbe@emory.edu.; Winship Cancer Institute of Emory University, Atlanta, Georgia.; The Cancer Animal Models Shared Resource., Marcus AI; Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia. aimarcu@emory.edu mmgilbe@emory.edu.; Winship Cancer Institute of Emory University, Atlanta, Georgia.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2018 Jan 15; Vol. 24 (2), pp. 420-432. Date of Electronic Publication: 2017 Dec 05.
DOI:	10.1158/1078-0432.CCR-17-1776
Abstrakt:	Purpose: 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. Experimental Design: We used the LSL-Kras G12D /Lkb1 fl/fl /Vim -/- model ( KLV -/- ), which incorporates a whole-body knockout of vimentin and is derived from the Cre-dependent LSL-Kras G12D /Lkb1 fl/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. Results: Characterization of KLV +/+ and KLV -/- mice shows that although 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. Conclusions: These data show that vimentin is required for lung adenocarcinoma metastasis by maintaining heterotypic tumor cell-CAF interactions during collective invasion. Clin Cancer Res; 24(2); 420-32. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu