Interferon-γ/Janus kinase 1/STAT1 signaling represses forkhead box A1 and drives a basal transcriptional state in muscle-invasive bladder cancer Journal Article


Authors: Lawrence, S. S.; Yamashita, H.; Shuman, L.; Raman, J. D.; Joshi, M.; Yochum, G. S.; Wu, X. R.; Al-Ahmadie, H. A.; Warrick, J. I.; Walter, V.; DeGraff, D. J.
Article Title: Interferon-γ/Janus kinase 1/STAT1 signaling represses forkhead box A1 and drives a basal transcriptional state in muscle-invasive bladder cancer
Abstract: During progression, luminal muscle-invasive bladder cancer (MIBC) can transition to the aggressive basal-squamous (Ba/Sq) subtype. Reduced expression of forkhead box A1 (FOXA1) in the urothelium is a hallmark and driver of the Ba/Sq transcriptional state and squamous differentiation. Ba/Sq tumors are highly inflamed; however, the specific inflammatory pathways contributing to the Ba/Sq state are unknown. In this study, transcriptomic analyses of The Cancer Genome Atlas MIBC cohort were performed to determine whether immune response gene signatures were associated with MIBC molecular states. Results showed that Ba/Sq MIBCs were enriched for the interferon-γ (IFN-γ)–dominant signature. Ba/Sq MIBCs exhibited increased IFN-γ/Janus kinase (JAK)/STAT pathway activity, corresponding to reduced FOXA1 regulon activity. Immunohistochemistry of MIBC specimens demonstrated that JAK1 expression was significantly increased in tumor areas with squamous differentiation. IFN-γ treatment of luminal MIBC cell lines significantly decreased the expression of luminal transcriptional drivers, including FOXA1, and increased the expression of Ba/Sq markers in a STAT1-dependent manner. RNA-sequencing analyses identified IFN-γ as a driver of the Ba/Sq state. The ability of IFN-γ to repress FOXA1 in luminal cells was abrogated by ruxolitinib inhibition of JAK1/2 activity. Additionally, pharmacologic inhibition or genetic ablation of JAK1 restored FOXA1 expression in Ba/Sq MIBC cells. These findings are the first to identify IFN-γ as an epithelial cell-extrinsic mechanism to repress FOXA1 and drive the Ba/Sq state in MIBC. © 2025 American Society for Investigative Pathology
Keywords: immunohistochemistry; controlled study; protein expression; human cell; cell function; stat1 protein; hepatocyte nuclear factor 3alpha; gene expression; cohort analysis; genetic association; enzyme activity; transcriptomics; immune response; gamma interferon; gene identification; gene repression; molecular pathology; muscle invasive bladder cancer; janus kinase 1; genetic damage; foxa1 gene; pharmacological parameters; ruxolitinib; human; article; rna sequencing; jak-stat signaling; bladder cancer cell line; type ii interferon signaling
Journal Title: American Journal of Pathology
Volume: 195
Issue: 5
ISSN: 0002-9440
Publisher: Elsevier Science, Inc.  
Date Published: 2025-05-01
Start Page: 1013
End Page: 1030
Language: English
DOI: 10.1016/j.ajpath.2025.01.013
PUBMED: 39986350
PROVIDER: scopus
PMCID: PMC12163414
DOI/URL:
Notes: Article -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors