title: Efficient extravasation of tumor-repopulating cells depends on cell deformability.
abstract: Cancer metastasis is the most deadly stage in cancer progression. Despite significant efforts over the past decades, it remains elusive why only a very small fraction of cancer cells is able to generate micrometastasis and metastatic colonization. Recently we have shown that tumor-repopulating cells (TRCs), a highly tumorigenic subpopulation of mouse melanoma cells, can be selected by being cultured and grown in 3D soft fibrin gels. Here we show that when injected into the yolk of a 2 day-post-fertilization (dpf) embryo of Tg (fli1:EGFP or kdrl:mCherry) zebrafish, TRCs are much more efficient in surviving and growing at various secondary sites to generate micrometastasis and metastatic colonization than control melanoma cells that are grown on rigid plastic. The metastasis of TRCs is dependent on the presence of Sox2, a self-renewal gene, and silencing Sox2 leads to the inhibition of TRC metastasis. High-resolution of 3D confocal images of the TRCs at the secondary sites show that extravasation and formation of micrometastases by TRCs are more efficient than by the control cells. Remarkably, efficient extravasation of TRCs in vivo and transmigration in vitro are determined by TRC deformability, as a result of low Cdc42 and high Sox2. Our findings suggest that tumor cell deformability is a key factor in controlling extravasation dynamics during metastasis.
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Junjian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Jia
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Yao
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Wei
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 China.|Department of Immunology, Institute of Basic Medical Sciences of Chinese Academy of Medical Sciences, Beijing 100005 China.
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.affiliation: Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Jia
authors.affiliation: Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, School of Life Sciences, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.|Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D008546:Melanoma, Experimental; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D055748:SOXB1 Transcription Factors; D020764:cdc42 GTP-Binding Protein