Diverse matrix metalloproteinase functions regulate cancer amoeboid migration

Abstract

Rounded-amoeboid cancer cells use actomyosin contractility driven by Rho-ROCK and JAK-STAT3 to migrate efficiently. It has been suggested that rounded-amoeboid cancer cells do not require matrix metalloproteinases (MMPs) to invade. Here we compare MMP levels in rounded-amoeboid and elongated-mesenchymal melanoma cells. Surprisingly, we find that rounded-amoeboid melanoma cells secrete higher levels of several MMPs, including collagenase MMP-13 and gelatinase MMP-9. As a result, rounded-amoeboid melanoma cells degrade collagen I more efficiently than elongated-mesenchymal cells. Furthermore, using a non-catalytic mechanism, MMP-9 promotes rounded-amoeboid 3D migration through regulation of actomyosin contractility via CD44 receptor. MMP-9 is upregulated in a panel of rounded-amoeboid compared with elongated-mesenchymal melanoma cell lines and its levels are controlled by ROCK-JAK-STAT3 signalling. MMP-9 expression increases during melanoma progression and it is particularly prominent in the invasive fronts of lesions, correlating with cell roundness. Therefore, rounded-amoeboid cells use both catalytic and non-catalytic activities of MMPs for invasion.

p53 regulates cytoskeleton remodeling to suppress tumor progression

“…Furthermore, it has recently been shown that CD44 binds to MMP9 and promotes rounded-amoeboid 3D migration by upregulating actomyosin contractility [187]. As previously discussed, the rounded-amoeboid migration of cancer cells does not require ECM degradation for invasion, so the catalytic activity of MMP9 is not necessary for promoting amoeboid 3D migration.…”

“…As previously discussed, the rounded-amoeboid migration of cancer cells does not require ECM degradation for invasion, so the catalytic activity of MMP9 is not necessary for promoting amoeboid 3D migration. However, the MMP9-CD44 axis leads to the increased expression of other MMPs, such as MMP13, by enhancing ROCK-JAK-STAT3 signaling, and this contributes to matrix degradation [187]. miR-200c can attenuate breast cancer cell invasion by targeting formin homology 2 domain-containing protein 1 (FHOD1), which induces actin filament nucleation and protein phosphatase, Mg 2?…”

New Insights into the Role of Podoplanin in Epithelial–Mesenchymal Transition

“…One is the increase in cellular motility driven by podoplanin interacting with the ERM proteins-Rho GTPases axis; the second is what we call "effective cohesiveness" in the cells. Effective cohesiveness designates a sensor mechanism or metabolite that would integrate the overall adhesive properties of a cell, and could be regulated by transcriptional and epigenetic mechanisms, protein stability, presence in the plasma membrane and context-specific mechanisms (like, for instance, the properties of the extracellular matrix) (Adhikary et al, 2014;Boulter et al, 2012;Engl et al, 2014;Friedl et al, 2014;Gueron et al, 2014;Marjoram et al, 2014;McGrail et al, 2014;Murali and Rajalingam, 2014;Orgaz et al, 2014;Sadok and Marshall, 2014;Thiery et al, 2012;50 Zegers and Friedl, 2014). If podoplanin is expressed in a cellular context with low effective cohesiveness, it will promote mesenchymal motility that will end up in EMT.…”

The stromal cell-surface protease fibroblast activation protein-α localizes to lipid rafts and is recruited to invadopodia

“…Although it remains elusive how FAPα exerts its functions in progression of these tumors it's evident, that a variety of different downstream pathways are involved [4]. There is increasing evidence of proteases being involved in protein complex formation [14][15][16]. We aimed at a holistic overview of the FAPα interactome and therefore applied the QUICK approach [18] using the CAF-derived cell line CT5.3.…”

“…At the same time, there is increasing evidence that proteases may exert their biological function in a non-enzymatic manner. Examples include involvement of matrix metalloproteases in cellular migration [14] and non-enzymatic functions of the cell surface serine protease prostasin [15,16]. Such observations make it essential to elucidate protease interactomes in order to better understand the molecular basis of their in vivo functions.…”