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<p>Plasticity transitions during carcinoma progression generate fetal-like progenitor states with metastatic capacity. How these progenitors emerge and persist during tumor progression remains unclear. Here, we elucidate a process that drives the emergence of SOX2<sup>+</sup> metastatic progenitors in lung adenocarcinomas (LUAD). LUAD cells at the tumor invasive front and distant metastases express the cell adhesion molecule L1CAM, a marker of regenerative epithelial progenitors and a mediator of cell-basement membrane and cell-cell interactions, as well as the proliferation of extravasated micrometastatic cells. We now identify a distinct and broader role of L1CAM as promoter of the SOX2<sup>+</sup> LUAD progenitor state. We show that L1CAM at cell-cell interfaces promotes the assembly of the planar cell polarity (PCP) complex in metastatic LUAD progenitors. L1CAM-dependent PCP acting through a non-canonical WNT signaling activates c-Jun, which cooperates with the chromatin remodeling factor CHD1 to drive <i>SOX2</i> expression and metastatic activity. This axis sustains the tumor-initiating and regenerative capacity of LUAD progenitor cells. By illuminating the role of L1CAM and PCP signaling in the generation of SOX2<sup>+</sup> LUAD progenitors, our findings identify potential new targets to treat metastatic cancer.</p>

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L1CAM signaling through planar cell polarity drives SOX2 expression and lung adenocarcinoma metastasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Jin Suk Park,
  • Yasemin Kaygusuz,
  • Carson Kenum,
  • Lan He,
  • Mohamed I. Gatie,
  • Xueqian Zhuang,
  • Roshan Sharma,
  • Ronan Chaligné,
  • Umesh K. Bhanot,
  • Richard P. Koche,
  • Tuomas Tammela,
  • Anna-Katerina Hadjantonakis,
  • Charles M. Rudin,
  • Joan Massagué

摘要

Plasticity transitions during carcinoma progression generate fetal-like progenitor states with metastatic capacity. How these progenitors emerge and persist during tumor progression remains unclear. Here, we elucidate a process that drives the emergence of SOX2+ metastatic progenitors in lung adenocarcinomas (LUAD). LUAD cells at the tumor invasive front and distant metastases express the cell adhesion molecule L1CAM, a marker of regenerative epithelial progenitors and a mediator of cell-basement membrane and cell-cell interactions, as well as the proliferation of extravasated micrometastatic cells. We now identify a distinct and broader role of L1CAM as promoter of the SOX2+ LUAD progenitor state. We show that L1CAM at cell-cell interfaces promotes the assembly of the planar cell polarity (PCP) complex in metastatic LUAD progenitors. L1CAM-dependent PCP acting through a non-canonical WNT signaling activates c-Jun, which cooperates with the chromatin remodeling factor CHD1 to drive SOX2 expression and metastatic activity. This axis sustains the tumor-initiating and regenerative capacity of LUAD progenitor cells. By illuminating the role of L1CAM and PCP signaling in the generation of SOX2+ LUAD progenitors, our findings identify potential new targets to treat metastatic cancer.