Song, Dae-Geun Lee, Gyu-Ho Nam, Seo Hee Cheong, Jin-Gyu Jeong, Doyoung Lee, Seo-Jin Pan, Cheol-Ho Jung, Jae Woo Kim, Hye-Jin Ryu, Jihye Kim, Ji Eon Kim, Somi Cho, Chang Yun Kang, Min-Kyung Lee, Kyung-Min Lee, Jung Weon 2024-01-20T00:30:40Z 2024-01-20T00:30:40Z 2021-09-03 2017-10-13 1949-2553 https://pubs.kist.re.kr/handle/201004/122172 Transmembrane 4 L six family member 5 (TM4SF5) is highly expressed in hepatocellular carcinoma tissues and enhances migration in two-dimensional environments. Here, we investigated how TM4SF5 is involved in diverse pro-metastatic phenotypes in in vivo-like three-dimensional (3D) extracellular matrix gels. TM4SF5-positive cells aggressively formed invasive foci in 3D Matrigel, depending on TM4SF5-mediated signaling activity, cytoskeletal organization, and matrix metallopeptidase (MMP) 2-mediated extracellular remodeling, whereas TM4SF5-null cells did not. The TM4SF5-null cells did, however, form invasive foci in 3D Matrigel following inhibition of Rho-associated protein kinase or addition of collagen I, suggesting that collagen I compensated for TM4SF5 expression. Similarly, TM4SF5-positive cells expressing vascular endothelial-cadherin formed network-like vasculogenic mimicry in 3D Matrigel and collagen I mixture gels, whereas TM4SF5-negative cells in the mixture gels displayed the network structures only upon further treatment with epidermal growth factor. The foci formation also required MMP2-mediated remodeling of the extracellular matrix. Co-cultures exhibited TM4SF5-positive or cancer-associated fibroblasts at the outward edges of TM4SF5-null cell clusters. Compared with TM4SF5-null cells, TM4SF5-positive cells in 3D collagen gels showed a more invasive outgrowth with dramatic invadopodia. These observations suggest that TM4SF5 plays roles in the promotion of diverse metastatic properties with fewer environmental requirements than TM4SF5-negative cells. English IMPACT JOURNALS LLC EPITHELIAL-MESENCHYMAL TRANSITION VASCULOGENIC MIMICRY CROSS-TALK CANCER CELLS EXPRESSION PHOSPHORYLATION MIGRATION ADHESION CULTURE TM4SF5 promotes metastatic behavior of cells in 3D extracellular matrix gels by reducing dependency on environmental cues Article 10.18632/oncotarget.17644 1 ONCOTARGET, v.8, no.48, pp.83480 - 83494 ONCOTARGET 8 48 83480 83494 scie scopus 000413030900010 2-s2.0-85030987493 Oncology Cell Biology Oncology Cell Biology Article EPITHELIAL-MESENCHYMAL TRANSITION VASCULOGENIC MIMICRY CROSS-TALK CANCER CELLS EXPRESSION PHOSPHORYLATION MIGRATION ADHESION CULTURE 3D cell culture TM4SF5 invasive foci microenvironment vasculogenic mimicry