FOXA2 promotes metastatic competence in small cell lung cancer Journal Article
| Authors: | Kawasaki, K.; Salehi, S.; Zhan, Y. A.; Chen, K.; Lee, J. H.; Salataj, E.; Zhong, H.; Manoj, P.; Kinyua, D.; Mello, B. P.; Sridhar, H.; Tischfield, S. E.; Linkov, I.; Ceglia, N.; Zatzman, M.; Havasov, E.; Shah, N. J.; Meng, F.; Loomis, B.; Bhanot, U. K.; Redin, E.; de Stanchina, E.; Hamard, P. J.; Koche, R. P.; McPherson, A.; Quintanal-Villalonga, Á.; Shah, S. P.; Massagué, J.; Rudin, C. M. |
| Article Title: | FOXA2 promotes metastatic competence in small cell lung cancer |
| 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. © The Author(s) 2025. |
| Keywords: | controlled study; human cell; promoter region; genetics; nonhuman; follow up; mouse; animal; metabolism; animals; mice; metastasis; gene expression; lung neoplasms; animal experiment; basic helix-loop-helix transcription factors; protein; pathology; cell line, tumor; lung tumor; gene expression regulation; liver metastasis; gene expression regulation, neoplastic; chromatin immunoprecipitation; promoter regions, genetic; tumor cell line; western blotting; brain metastasis; neoplasm metastasis; ovary metastasis; small cell lung cancer; small cell lung carcinoma; adrenal metastasis; basic helix loop helix transcription factor; enhancer region; hepatocyte nuclear factor 3beta; hepatocyte nuclear factor 3-beta; rna isolation; disease incidence; transcription factor mash1; cell component; cancer; humans; human; male; female; article; rna sequencing; differential gene expression; induced response; ascl1 protein, human; prospero homeobox protein 1; foxa2 protein, human |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-05-26 |
| Start Page: | 4865 |
| Language: | English |
| DOI: | 10.1038/s41467-025-60141-5 |
| PUBMED: | 40419484 |
| PROVIDER: | scopus |
| PMCID: | PMC12106783 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grnat (P30 CA008748) acknowledged in PDF -- MSK corresponding authors are Joan Massagué and Charles Rudin -- Source: Scopus |
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