Imaging of collectively invading cocultures of carcinoma cells and stromal fibroblasts reveals that the leading cell is always a fibroblast and that carcinoma cells move within tracks in the extracellular matrix behind the fibroblast. The generation of these tracks by fibroblasts is sufficient to enable the collective invasion of the squamous cell carcinoma (SCC) cells and requires both protease- and force-mediated matrix remodelling. Force-mediated matrix remodelling depends on integrins alpha3 and alpha5, and Rho-mediated regulation of myosin light chain (MLC) activity in fibroblasts, but these factors are not required in carcinoma cells. Instead, carcinoma cells use Cdc42 and MRCK (myotonic dystrophy kinase-related CDC42-binding protein kinases) mediated regulation of MLC to follow the tracks generated by fibroblasts.
Proinflammatory cytokines are frequently observed in the tumor microenvironment, and chronic inflammation is involved in cancer initiation and progression. We show that cytokine signaling through the receptor subunit GP130-IL6ST and the kinase JAK1 generates actomyosin contractility through Rho-kinase dependent signaling. This pathway generates contractile force in stromal fibroblasts to remodel the extracellular matrix to create tracks for collective migration of squamous carcinoma cells and provides the high levels of actomyosin contractility required for migration of individual melanoma cells in the rounded, "amoeboid" mode. Thus, cytokine signaling can generate actomyosin contractility in both stroma and tumor cells. Strikingly, actomyosin contractility itself positively modulates activity of the transcription factor STAT3 downstream of JAK1, demonstrating positive feedback within the signaling network.
Rho GTPases control cytoskeletal dynamics through cytoplasmic effectors, and regulate transcriptional activation by the Myocardin Related Transcription Factors (MRTFs), coactivators for Serum Response Factor (SRF). We used RNAi to investigate the contribution of the MRTF-SRF pathway to cytoskeletal dynamics in MDA-MB-231 breast carcinoma and B16F2 melanoma cells, where basal MRTF-SRF activity is Rho-dependent. Depletion of MRTFs or SRF reduces cell adhesion, spreading, invasion and motility in culture, without affecting proliferation or inducing apoptosis; MRTF-depleted tumor cell xenografts exhibit reduced cell motility but proliferate normally. MRTF- and SRF-depleted tumor cells fail to colonise the lung from the bloodstream, being unable to persist following their initial arrival at the lung. Only a few genes exhibit MRTF-dependent expression in both cell lines. Two of these, MYH9 (MLC2) and MYL9 (NMHCIIa), are also required for invasion and lung colonisation. Conversely, expression of an activated MRTF increases lung colonisation by poorly metastatic B16F0 cells. Actin-based cell behaviour and experimental metastasis thus requires Rho-dependent nuclear signalling through the MRTF-SRF network.
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