FOXA2 promotes metastatic competence in small cell lung cancer
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.
Authors
- Harsha Sridhar (ORCID: https://orcid.org/0009-0000-3273-1367)
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Matthew Zatzman (ORCID: https://orcid.org/0000-0001-5235-4116)
- Esther Redín (ORCID: https://orcid.org/0000-0001-9539-7298)
- Eliyahu Havasov
- Àlvaro Quintanal-Villalonga (ORCID: https://orcid.org/0000-0002-7234-3446)
- Sohrab P. Shah (ORCID: https://orcid.org/0000-0001-6402-523X)
- Kenta Kawasaki (ORCID: https://orcid.org/0000-0002-0063-2257)
- Pierre-Jacques Hamard (ORCID: https://orcid.org/0000-0002-2484-6161)
- Brian Houck‐Loomis (ORCID: https://orcid.org/0000-0002-1863-1199)
- Nicholas Ceglia (ORCID: https://orcid.org/0000-0001-9387-103X)
- Barbara Vaz de Mello (ORCID: https://orcid.org/0000-0001-6688-8119)
- Charles M. Rudin (ORCID: https://orcid.org/0000-0001-5204-3465)
- Andrew McPherson (ORCID: https://orcid.org/0000-0002-5654-5101)
- Eralda Salataj (ORCID: https://orcid.org/0000-0001-8661-1686)
- Joan Massagué (ORCID: https://orcid.org/0000-0001-9324-8408)
- Neil J. Shah (ORCID: https://orcid.org/0000-0001-5752-6212)
- Parvathy Manoj (ORCID: https://orcid.org/0000-0002-1121-0121)
- Irina Linkov (ORCID: https://orcid.org/0000-0001-7520-5359)
- Richard P. Koche (ORCID: https://orcid.org/0000-0002-6820-5083)
- Sam E. Tischfield
- Fanli Meng (ORCID: https://orcid.org/0000-0002-7276-9842)
- Yingqian A. Zhan (ORCID: https://orcid.org/0000-0002-3548-9227)
- Umesh Bhanot (ORCID: https://orcid.org/0000-0001-6656-1239)
- Dennis Kinyua
- Kevin Yanjun Chen (ORCID: https://orcid.org/0000-0002-3851-6016)
- Jun Ho Lee (ORCID: https://orcid.org/0000-0002-0131-1527)
- Hong Zhong (ORCID: https://orcid.org/0000-0002-9931-7504)
- Sohrab Salehi (ORCID: https://orcid.org/0009-0008-8276-1765)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- Molecular Oncology (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-26
- DOI
- https://doi.org/10.1038/s41467-025-60141-5
- Citations
- 5
- Primary Topic
- Lung Cancer Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 5.23
Funders
- Van Andel Research Institute
- Memorial Sloan-Kettering Cancer Center
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
- Weill Cornell Medical College
- Stand Up To Cancer
- National Cancer Institute