FOXA2 promotes metastatic competence in small cell lung cancer

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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60141-5

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