Abstract
Overexpression of Mdmx hastened leukemogenesis by upregulating WNT–β-catenin signaling in vivo
Major Finding: Overexpression of some essential genes for metastasis led to cell stiffness–based immunosurveillance.
Concept: These genes encode isoforms of a transcription factor that regulates expression of cytoskeletal genes.
Impact: This study reveals that immunosurveillance by cytotoxic T lymphocytes has a mechanical component.
To acquire metastatic capabilities, cancer cells must undergo cytoskeletal alterations. These changes are mediated in part by myocardin-like transcription factors (MRTF) A and B, which promote transcription of the genes encoding G-actin and other cytoskeletal components. Tello-Lafoz and colleagues found that metastatic colonization by melanoma or breast cancer cells was reduced by Mrtfa or Mrtfb knockdown, as expected. However, in seeming contradiction with the two MRTF isoforms' essentiality for metastatic seeding, Mrtfb overexpression also compromised the cancer cells' metastatic potential. This phenotype was suppressed by depletion of natural killer cells or CD8+ T cells, suggesting a role for immunosurveillance by these lymphocytes in constraining metastasis by Mrtfb-overexpressing tumor cells. Consistent with this notion, in vitro experiments showed Mrtfa or Mrtfb overexpression rendered cancer cells more sensitive to cytotoxic T lymphocyte–mediated killing, with each immune synapse formed being more likely to induce (and more rapidly promoting) cancer cell death. Mechanistically, Mrtfa or Mrtfb overexpression led to increased levels of transcripts encoding actins and other cytoskeletal proteins, suggesting a possible role for MRTF-mediated cytoskeletal changes in the higher immunogenicity of cancer cells overexpressing either of these genes. Accordingly, atomic force microscopy experiments showed that overexpression of Mrtfa or Mrtfb rigidified cancer cells both on average and at peak stiffness levels, effects that were diminished in the presence of an F-actin depolymerizing agent. Further experiments confirmed that it was not cell-surface features, but rather cellular features generated by components enclosed by the plasma membrane—presumably the actin cytoskeleton—that caused Mrtfa- and Mrtfb-overexpressing cancer cells to be more susceptible to immune control. Correspondingly, expression of a Salmonella enterica gene encoding a protein that severs F-actin reduced cell stiffness and abolished the increased sensitivity to cytotoxic T lymphocyte–mediated killing otherwise observed with Mrtfa or Mrtfb overexpression in cancer cells. Collectively, these findings support the idea that mechanical sensing is an important component of immunosurveillance that may act to suppress metastasis.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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