Hypoxia-induced invadopodia formation: a role for β-PIX

Abstract

During tumour progression, oxygen tension in the microenvironment surrounding tumour cells is reduced, resulting in hypoxia. It is well established that cancer cells resist the negative effects of hypoxia by inducing angiogenesis predominantly via the activity of transcription factor hypoxia-inducible factor-1 (HIF-1). However, more recently HIF-1α has also been linked to increased invasive potential, although the molecular mechanisms remain to be defined. Invasive cancer cells are thought to employ membrane protrusions, termed invadopodia, to achieve matrix degradation. While many invadopodia components have been identified, signalling pathways that link extracellular stimuli to invadopodia formation remain largely unknown. Indeed, the relationship between invadopodia formation and HIF-1α has not been explored. We now report that HIF-1α is a driver of invadopodia formation. Furthermore, we have identified an important, direct and novel link between the Rho family activator β-PIX, HIF-1α and invadopodia formation. Indeed, we find that β-PIX expression is essential for invadopodia formation. In conclusion, we identify a new HIF-1α mechanistic pathway and suggest that β-PIX is a novel downstream signalling mediator during invadopodia formation.

Direct visualization of the phenotype of hypoxic tumor cells at single cell resolution in vivo using a new hypoxia probe

“…S6C). This finding is also similar to what was observed in DMOG treated MDA-MB-231 cells by others 70 …”

Digging a little deeper: The stages of invadopodium formation and maturation

“…A number of Cdc42 GEFs have been implicated in invadopodium formation, including Vav1, β-PIX and Fgd1 (Ayala et al, 2009; Md Hashim et al, 2013; Razidlo et al, 2014). Recently, Src has been shown to activate Vav1, which, in turn, activates Cdc42 to induce invadopodium formation (Razidlo et al, 2014).…”

“…Recently, Src has been shown to activate Vav1, which, in turn, activates Cdc42 to induce invadopodium formation (Razidlo et al, 2014). β-PIX is essential for hypoxia-induced invadopodium formation, while the Cdc42-specific GEF Fgd1 also promotes invadopodium formation (Ayala et al, 2009; Md Hashim et al, 2013). Interestingly, as all three GEFs are activated by EGF-induced Src phosphorylation (Feng et al, 2010; Miyamoto et al, 2003; Razidlo et al, 2014), it is tempting to speculate that the EGFR-Src-GEF-Cdc42 axis may represent a major pathway for initiation of invadopodium precursor assembly (Figure 2).…”

Regulation of invadopodia by the tumor microenvironment

“…1). 62,81,82 In the study using HNSCC, lung, and pancreatic cancer cells mentioned earlier, hypoxia-induced invadopodia formation and ECM degradation were shown to be dependent upon HIF-1α. 62 In another study, both HIF-1α and HIF-2α increase melanoma invasion by promoting invadopodia formation through activation of PDGF receptor-α (PDGFRα) and Src, respectively, and coordinating ECM degradation through MT1-MMP and MMP-2 expression.…”

“…82 Finally, in breast cancer cells, invadopodia formation and function downstream of HIF-1α is dependent upon expression of the Rho family activator, p-21 activated protein kinase-interacting exchange factor (β-PIX). 81 HIF-1α also regulates invadopodia through epithelial-mesenchymal transition (EMT)-promoting transcription factors, such as Twist. Twist induces invadopodia formation through PDGFRα-mediated activation of Src and is directly regulated by HIF-1α to promote metastasis.…”