Interferon-γ/Janus Kinase 1/STAT1 Signaling Represses Forkhead Box A1 and Drives a Basal Transcriptional State in...

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Muscle-invasive bladder cancer (MIBC) can progress to the aggressive basal-squamous (Ba/Sq) subtype.
• Reduced forkhead box A1 (FOXA1) expression is a key feature of the Ba/Sq state and squamous differentiation.
• The inflammatory pathways driving the Ba/Sq subtype in MIBC remain largely unknown.

Purpose of the Study:

• To investigate the association between immune response gene signatures and MIBC molecular states.
• To identify specific inflammatory pathways contributing to the Ba/Sq subtype.
• To elucidate the role of interferon-gamma (IFN-γ) in driving the Ba/Sq state and regulating FOXA1.

Main Methods:

• Transcriptomic analyses of The Cancer Genome Atlas (TCGA) MIBC cohort.
• Immunohistochemistry of MIBC specimens to assess JAK1 expression.
• In vitro studies involving IFN-γ treatment of luminal MIBC cell lines.
• RNA-sequencing to identify drivers of the Ba/Sq state.
• Pharmacologic inhibition and genetic ablation of JAK1/2 activity.

Main Results:

• Ba/Sq MIBCs were enriched for an interferon-γ (IFN-γ)-dominant immune signature.
• Increased IFN-γ/Janus kinase (JAK)/STAT pathway activity correlated with reduced FOXA1 expression in Ba/Sq tumors.
• IFN-γ treatment decreased FOXA1 and increased Ba/Sq markers in a STAT1-dependent manner.
• JAK1/2 inhibition abrogated IFN-γ's ability to repress FOXA1.
• JAK inhibition restored FOXA1 expression in Ba/Sq MIBC cells.

Conclusions:

• IFN-γ acts as an epithelial cell-extrinsic factor that represses FOXA1, driving the basal-squamous (Ba/Sq) subtype in muscle-invasive bladder cancer (MIBC).
• The IFN-γ/JAK/STAT pathway is a critical driver of the Ba/Sq state.
• Targeting the JAK/STAT pathway may represent a therapeutic strategy to restore FOXA1 expression and combat Ba/Sq MIBC.