TRIM27/MRTF-B-Dependent Integrin β1 Expression Defines Leading Cells in Cancer Cell Collectives

Abstract

For collective invasion, cancer cells form cohesive groups comprised of leading cells (LCs) at the forefront and following cells (FCs) at the rear. However, the molecular mechanisms that define LCs and FCs remain elusive. Here, we demonstrated that LCs, but not FCs, upregulated the expression of integrin β1 after the loss of intercellular adhesion. The LC-specific expression of integrin β1 was posttranscriptionally regulated by the TRIM27/MRTF-B complex in response to the loss of intercellular adhesion, thereby regulating the stability and translation of integrin β1 mRNA via microRNA-124 in LCs. Accordingly, depletion of TRIM27 and MRTF-B abrogated the upregulation of integrin β1 in LCs and blocked the invasion of cancer cell groups in vitro and in vivo. Therefore, our findings revealed that the specific function of LCs was defined by intrinsic mechanisms related to the presence of the cell's free surface, providing insights into the regulation of intratumor heterogeneity.

Potential involvement of kinesin-1 in the regulation of subcellular localization of Girdin

“…Finally, Girdin expression was also detected in cancer tissues including breast carcinoma and glioblastoma [5,6]. Given recent consensus that most cancer cells undergo collective invasion rather than single cell invasion into the stroma [23,24], it would be interesting to investigate whether Girdin is involved in the common pathway of collective migration of cancer cells and neuroblasts.…”

TRIM27 (tripartite motif containing 27)

“…TRIM27 interacts with MAGE-L2 protein and ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport (Hao et al, 2013). MRTF-B/TRIM27 complex plays a role in the regulation of integrin b1 expression via Rho and miR-124 in Leading Cells (LCs) among migrating cancer cell groups following loss of intracellular adhension (Kato et al, 2014 Zoumpoulidou G, Mittnacht S Atlas Genet Cytogenet Oncol Haematol. 2015;19(4) …”

Making Heads or Tails of It: Cell–Cell Adhesion in Cellular and Supracellular Polarity in Collective Migration

“…In leader cells, MRTF-B translocates to the nucleus on activation of RhoA, which is induced by the loss of E-cadherin-based junctions. In the nucleus, MRTF-B interacts with Trim27 and up-regulates b1-integrin expression by inhibiting the b1-integrin-specific miRNA-124 (Kato et al 2014;Gjorevski et al 2015). Previous work has implicated MRTFs as cofactor of serum response factor (SRF) in transcriptional regulation of many actin regulators involved in cell migration downstream from Rho GTPases (Olson and Nordheim 2010).…”

“…The increase of b1-integrin expression in leader cells involves adherens junction -dependent transcriptional regulation via the myocardin-related transcription factor (MRTF) (Kato et al 2014). MRTF is retained in the cytoplasm by monomeric G-actin, and translocates to the nucleus on a decrease of G-actin resulting from increased actin polymerization.…”

“…Dll4 can also be induced via a mechanism involving the deposition of laminin a4 Stenzel et al 2011) or by local reduction of mechanical stress in migrating epithelial sheets (Riahi et al 2015), indicating conserved roles for this pathway in leader cell selection. Proteins promoting leader cell migration include Mipp, NRP1, podoplanin, and fascin, which promote filopodial invasion (Wicki et al 2006;Vignjevic et al 2007;Cheng and Andrew 2015;Fantin et al 2015), whereas elevated expression of b1-integrin (Hegerfeldt et al 2002;Kato et al 2014;Yamaguchi et al 2015) promotes migration by enhancing traction on the substrate.…”