Major finding: Cytokine signaling via JAK1 and ROCK generates contractile force to promote cell migration.
Impact: Characterization of the underlying signaling mechanisms will lead to a better understanding of metastasis.
Clinical relevance: Cytokine or JAK/STAT pathway inhibitors may be useful in blocking invasion and metastasis.
The force generated by actin and myosin (actomyosin) contractility is crucial for tumor cell migration. Highly contractile tumor cells move in a rounded, “amoeboid” manner due to an ability to deform the extracellular matrix and exhibit the mechanical strength to resist shear forces associated with entry into the blood supply. Contractile force is also required for stromal cells to remodel the extracellular matrix and create tracks along which aggregates of cancer cells can invade surrounding tissue. However, the signaling pathways responsible for generation of actomyosin contractility in tumor and stromal cells are not well characterized. A collaboration of the Marshall and Gaggioli groups now demonstrates that JAK1-mediated cytokine signaling, a component of the inflammatory response, regulates contractile forces in both tumor and stromal cells. In response to inflammation, cytokine receptors activate JAK1, which phosphorylates multiple substrates, including STAT transcription factors. Phosphorylation of regulatory myosin light-chain 2 (MLC2), which is required for myosin II-mediated contraction, also occurs downstream of JAK1, and plays a role in actomyosin contractility and migration in squamous cell carcinoma and melanoma cell lines. Interestingly, the Rho kinase ROCK, a known contributor to actomyosin contractility, is required for STAT3 phosphorylation and activation, suggesting that a positive feedback mechanism drives cell contractility and cytokine signaling. To determine the clinical relevance of these findings, STAT3 expression and cell morphology was assayed in 19 primary human melanomas and 16 metastases. High STAT3 expression was associated with a contractile phenotype, demonstrated by a round cell morphology. Round cells with high STAT3 intensity predominated at the invasive front of tumors and often comprised the majority of metastases. These findings extend our understanding of the link between inflammation and cancer and identify potential therapeutic targets for metastatic cancers.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details.
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