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<p>Different forms of epithelial-to-mesenchymal transition (EMT) manifest during tumor progression. Little is known about the mechanistic basis and functional role of these distinct EMTs. We explored this question in lung adenocarcinoma (LUAD) primitive progenitors, which are competent to enter dormancy in response to transforming growth factor-β (TGFβ) upon metastatic dissemination. The TGFβ response in these cells includes growth arrest and a full EMT that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGFβ drives this transition by inducing expression of the actin depolymerizing protein gelsolin, which converts a migratory, stress-fiber-rich phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors and protects them from killing by cytotoxic lymphocytes. Gelsolin-deficient LUAD progenitors can enter dormancy but succumb to immune surveillance. Thus, quiescent LUAD metastatic progenitors undergo an atypical EMT to avert immune surveillance during TGFβ-driven metastatic dormancy.</p>

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TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月5日

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  • Zhenghan Wang,
  • Yassmin Elbanna,
  • Inês Godet,
  • Siting Gan,
  • Lila Peters,
  • George Lampe,
  • Yanyan Chen,
  • Joao Xavier,
  • Morgan Huse,
  • Joan Massagué

摘要

Different forms of epithelial-to-mesenchymal transition (EMT) manifest during tumor progression. Little is known about the mechanistic basis and functional role of these distinct EMTs. We explored this question in lung adenocarcinoma (LUAD) primitive progenitors, which are competent to enter dormancy in response to transforming growth factor-β (TGFβ) upon metastatic dissemination. The TGFβ response in these cells includes growth arrest and a full EMT that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGFβ drives this transition by inducing expression of the actin depolymerizing protein gelsolin, which converts a migratory, stress-fiber-rich phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors and protects them from killing by cytotoxic lymphocytes. Gelsolin-deficient LUAD progenitors can enter dormancy but succumb to immune surveillance. Thus, quiescent LUAD metastatic progenitors undergo an atypical EMT to avert immune surveillance during TGFβ-driven metastatic dormancy.