Journal Article

FOXA2 promotes metastatic competence in small cell lung cancer

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

2025

Overview

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. Small cell lung cancer presents high and multi-site metastatic potential. Here, the authors discover that FOXA2, regulated by ASCL1, promotes multi-site metastasis in small cell lung cancer by inducing a fetal neuroendocrine gene expression program.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/109 / 13/95 / 38/23 / 38/39 / 38/5 / 38/91 / 59/5 / 631/67/1612/2143 / 64/60 / 692/4028/67/322 / Animals / ASCL1 protein / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - metabolism / Cell Line, Tumor / Diagnosis / Female / Fetuses / Gene expression / Gene Expression Regulation, Neoplastic / Hepatocyte Nuclear Factor 3-beta - genetics / Hepatocyte Nuclear Factor 3-beta - metabolism / Humanities and Social Sciences / Humans / Lung cancer / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Male / Metastases / Metastasis / Mice / multidisciplinary / Neoplasm Metastasis / Promoter Regions, Genetic / Science / Science (multidisciplinary) / Small cell lung carcinoma / Small Cell Lung Carcinoma - genetics / Small Cell Lung Carcinoma - metabolism / Small Cell Lung Carcinoma - pathology / Transcription factors / Tumorigenesis