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<p>Small cell lung cancer (SCLC) is known for its high metastatic potential, with most patients demonstrating clinically evident metastases in multiple organs at diagnosis. The factors contributing to this exceptional metastatic capacity have not been defined. To bridge this gap, we compare gene expression in SCLC patient samples who never experienced metastasis or relapse throughout their clinical course, versus primary SCLC patient samples from more typical patients who had metastatic disease at diagnosis. This analysis identifies FOXA2 as a transcription factor strongly associated with SCLC metastasis. Subsequent analyses in experimental models demonstrates that FOXA2 induces a fetal neuroendocrine gene expression program and promotes multi-site metastasis. Moreover, we identify ASCL1, a transcription factor known for its initiating role in SCLC tumorigenesis, as a direct binder of the <i>FOXA2</i> promoter and regulator of <i>FOXA2</i> expression. Taken together, these data define the ASCL1-FOXA2 axis as a critical driver of multiorgan SCLC metastasis.</p>

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FOXA2 promotes metastatic competence in small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月26日

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  • Kenta Kawasaki,
  • Sohrab Salehi,
  • Yingqian A. Zhan,
  • Kevin Chen,
  • Jun Ho Lee,
  • Eralda Salataj,
  • Hong Zhong,
  • Parvathy Manoj,
  • Dennis Kinyua,
  • Barbara P. Mello,
  • Harsha Sridhar,
  • Sam E. Tischfield,
  • Irina Linkov,
  • Nicholas Ceglia,
  • Matthew Zatzman,
  • Eliyahu Havasov,
  • Neil J. Shah,
  • Fanli Meng,
  • Brian Loomis,
  • Umesh K. Bhanot,
  • Esther Redin,
  • Elisa de Stanchina,
  • Pierre-Jacques Hamard,
  • Richard P. Koche,
  • Andrew McPherson,
  • Álvaro Quintanal-Villalonga,
  • Sohrab P. Shah,
  • Joan Massagué,
  • Charles M. Rudin

摘要

Small cell lung cancer (SCLC) is known for its high metastatic potential, with most patients demonstrating clinically evident metastases in multiple organs at diagnosis. The factors contributing to this exceptional metastatic capacity have not been defined. To bridge this gap, we compare gene expression in SCLC patient samples who never experienced metastasis or relapse throughout their clinical course, versus primary SCLC patient samples from more typical patients who had metastatic disease at diagnosis. This analysis identifies FOXA2 as a transcription factor strongly associated with SCLC metastasis. Subsequent analyses in experimental models demonstrates that FOXA2 induces a fetal neuroendocrine gene expression program and promotes multi-site metastasis. Moreover, we identify ASCL1, a transcription factor known for its initiating role in SCLC tumorigenesis, as a direct binder of the FOXA2 promoter and regulator of FOXA2 expression. Taken together, these data define the ASCL1-FOXA2 axis as a critical driver of multiorgan SCLC metastasis.