The orthologous Tbx transcription factors Omb and TBX2 induce epithelial cell migration and extrusionin vivowithout involvement of matrix metalloproteinases

Abstract

The transcription factors TBX2 and TBX3 are overexpressed in various human cancers. Here, we investigated the effect of overexpressing the orthologous Tbx genes Drosophila optomotor-blind (omb) and human TBX2 in the epithelium of the Drosophila wing imaginal disc and observed two types of cell motility. Omb/TBX2 overexpressing cells could move within the plane of the epithelium. Invasive cells migrated long-distance as single cells retaining or regaining normal cell shape and apico-basal polarity in spite of attenuated apical DE-cadherin concentration. Inappropriate levels of DE-cadherin were sufficient to drive cell migration in the wing disc epithelium. Omb/TBX2 overexpression and reduced DE-cadherin-dependent adhesion caused the formation of actin-rich lateral cell protrusions. Omb/TBX2 overexpressing cells could also delaminate basally, penetratingthe basal lamina, however, without degradation of extracellular matrix. Expression of Timp, an inhibitor of matrix metalloproteases, blocked neither intraepithelial motility nor basal extrusion. Our results reveal an MMP-independent mechanism of cell invasion and suggest a conserved role of Tbx2-related proteins in cell invasion and metastasis-related processes.

Essential Roles of Tbr1 in the Formation and Maintenance of the Orientation-Selective J-RGCs and a Group of OFF-Sustained RGCs in Mouse

“…T-box TFs play important roles in multiple developmental processes that involve extensive cell migration and cell-cell and cell-environment interactions, including trophoblast-uterus interaction during implantation, mesoderm migration during gastrulation, and T-cell formation and maturation (Strumpf et al, 2005, Russ et al, 2000, Costello et al, 2011, Nowotschin et al, 2013, Shen et al, 2014, Pearce et al, 2003, Ciruna and Rossant, 2001). These processes require discrete cell adhesion molecules (CAMs) to establish and maintain the specific interactions, and T-box TFs have been shown to regulate specific CAMs in these processes and tumor metastasis (Yamamoto et al, 1998, Hasson et al, 2010, Rodriguez et al, 2008, Sun et al, 2014).…”

The transcription factor spalt and human homologue SALL4 induce cell invasion via the dMyc-JNK pathway in Drosophila

“…Coexpression of the membrane marker CD8-GFP with sal showed that the migrating cells had filopodia-like structures ( Fig. 1I), which is a property of migratory and invasive cells (Shen et al, 2014). Taken together, our results demonstrate that the Drosophila salm, salr and human SALL4 are highly conserved in stimulating cell proliferation and cell motility in the wing disc.…”

“…When sal/SALL4 was overexpressed, some clone cells were dispersed to the single cell level (Fig. 1F,G, red arrowheads), which is similar to expressing another Dpp target gene optomotorblind (Shen et al, 2014), indicating increased mobility of sal/ SALL4-expressing cells. Tumor-like proliferating cell clusters were seen in the hinge region ( Fig.…”

Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression

“…TBX2/3 can contribute to transformation by suppressing senescence and anoikis ( 5 , 12 – 16 ). TBX2/3 can promote epithelial–mesenchymal transition (EMT) and invasive cell behavior in melanoma and breast cancer cells ( 6 , 10 , 17 , 18 ) and in heterospecific epithelia ( 19 ). TBX2/3 may also contribute to breast cancer growth by promoting proliferation of cancer stem-like cells ( 20 , 21 ).…”

“…In Drosophila , the only Tbx2 subfamily gene is optomotor-blind ( omb , FlyBase: bifid, bi ) ( 50 ). Overexpression of omb or TBX2 in an epithelium of the developing fly, the wing imaginal disk, causes two types of cellular motility: migration in the plane of the epithelium and basal delamination with penetration of the basal membrane ( 19 ). Omb also controls cell proliferation in a context-dependent manner ( 51 , 52 ).…”