FOXA2 promotes metastatic competence in small cell lung cancer
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.
Article Details
Authors (29)
Kenta Kawasaki
Sohrab Salehi
Yingqian A. Zhan
Kevin Chen
Jun Ho Lee
Department of Materials Science and Engineering
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