ArticleNature communications2022
FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation.
Erratum issuedOpen access · goldAbstract read
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Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 31 papers.
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31citing papers in PubMed
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Who cites it
31 citing papers in PubMed, 37 citations in OpenAlex.
- Cell plasticity in cancer and therapy resistance.Experimental & molecular medicine · 2026Review
- A Spatial Atlas of Muscle-Invasive Bladder Cancer Reveals Lineage-Specific Vulnerabilities and Immune Architecture.Cancer discovery · 2026Article
- Histological Subtypes and Divergent Differentiation of Urothelial Carcinoma: Histology, Genomics, and Management Implications.European urology · 2026Review
- FOXA1 is a highly sensitive diagnostic marker for prostate cancer including small cell carcinoma of the prostate.Histopathology · 2026Article
- Recurrence in the chemotherapy regimen of bladder carcinoma originates from quiescent epidermoid-like cells.Nature communications · 2026Article
- FOXA1 loss drives basal/squamous de-differentiation of prostate cancer and induces an immunosuppressive tumor microenvironment.Nature communications · 2026Article
- Integration of bulk and single-cell transcriptomic sequencing reveals the neutrophil heterogeneity in bladder cancer and establishes a prognostic model.Discover oncology · 2026Article
- Mechanisms and implications of epithelial cell plasticity in the bladder.Nature reviews. Urology · 2026Review
- APOBEC3 promotes squamous differentiation via IL-1A/AP-1 signaling.Nature communications · 2025Article
- Clinical Outcomes, Genomic Heterogeneity, and Therapeutic Considerations Across Histologic Subtypes of Urothelial Carcinoma.European urology · 2025Article
- Bladder cancer subtypes exhibit limited plasticity across different microenvironments and in metastases.Experimental hematology & oncology · 2025Article
- Article
- PTEN loss drives p53 LOH and immune evasion in a novel urothelial organoid model harboring p53 missense mutations.Oncogene · 2025Article
- Interferon-γ/Janus Kinase 1/STAT1 Signaling Represses Forkhead Box A1 and Drives a Basal Transcriptional State in Muscle-Invasive Bladder Cancer.The American journal of pathology · 2025Article
- Different PD-L1 Assays Reveal Distinct Immunobiology and Clinical Outcomes in Urothelial Cancer.Cancer immunology research · 2025Article
- Tracing the Evolution of Sex Hormones and Receptor-Mediated Immune Microenvironmental Differences in Prostate and Bladder Cancers: From Embryonic Development to Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- SE-lncRNAs in Cancer: Classification, Subcellular Localisation, Function and Corresponding TFs.Journal of cellular and molecular medicine · 2024Review
- FOXA1 enhances antitumor immunity via repressing interferon-induced PD-L1 expression in nasopharyngeal carcinoma.Journal for immunotherapy of cancer · 2024Article
- Article
- miRNome targeting NF-κB signaling orchestrates macrophage-triggered cancer metastasis and recurrence.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
Corrections and comments
- Erratum issued
Authors and funding
51 authors at 9 institutions in 3 countries.
Joshua I Warrick *Department of Pathology and Laboratory Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA.ORCID http://orcid.org/0000-0001-6149-1331
Wenhuo Hu *Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-8686-7160
Hironobu Yamashita *Department of Pathology and Laboratory Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Vonn WalterDepartment of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA.ORCID http://orcid.org/0000-0001-6114-6714
Lauren ShumanDepartment of Pathology and Laboratory Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA.ORCID http://orcid.org/0000-0003-2383-2240
Jenna M CraigDepartment of Pathology and Laboratory Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Lan L GellertDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Mauro A A CastroBioinformatics and Systems Biology Laboratory, Federal University of Parana, Curitiba, Paraná, Brazil.
A Gordon RobertsonBC Cancer, Canada's Michael Smith Genome Sciences Centre, Vancouver, BC, Canada.
Fengshen KuoUrology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0003-1797-2896
Irina OstrovnayaDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Judy SarungbamDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ying-Bei ChenDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0001-5207-3648
Anuradha GopalanDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sahussapont J SirintrapunDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Samson W FineDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-4322-3736
Satish K TickooDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-9775-0478
Kwanghee KimUrology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0003-0544-6792
Jasmine ThomasUrology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nagar KaranUrology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sizhi Paul GaoHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Timothy N ClintonUrology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-0616-6840
Andrew T LenisUrology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0001-9413-7793
Timothy A ChanHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-9265-0283
Ziyu ChenHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-1198-1516
Manisha RaoHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Travis J HollmanDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0003-1599-0433
Yanyun LiDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nicholas D SocciMarie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Shweta ChavanMarie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Agnes VialeMarie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Neeman MohibullahMarie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Bernard H BochnerUrology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Eugene J PietzakUrology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Min Yuen TeoDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0003-2511-6731
Gopa IyerDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-5093-6099
Jonathan E RosenbergDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Dean F BajorinDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0003-4001-7088
Matthew KaagDepartment of Urology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Suzanne B MerrillDepartment of Urology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Monika JoshiDepartment of Medicine, Division of Hematology-Oncology, Penn State Cancer Institute, Hershey, PA, USA.
Rosalyn AdamDepartment of Urology, Boston Children's Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-0943-6236
John A TaylorDepartment of Urology, University of Kansas Medical Center, Kansas City, MO, USA.
Peter E ClarkLevine Cancer Institute, Atrium Health, Charlotte, NC, USA.
Jay D RamanDepartment of Urology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Victor E ReuterDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Yu ChenHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-0171-3884
Samuel A FuntMarie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-7235-6319
David B SolitHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-6614-802X
David J DeGraffDepartment of Pathology and Laboratory Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA. ddegraff@pennstatehealth.psu.edu.ORCID http://orcid.org/0000-0002-7154-7594
Hikmat A Al-AhmadieDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. alahmadh@mskcc.org.ORCID http://orcid.org/0000-0002-2938-6627
Memorial Sloan Kettering Cancer Center · USPennsylvania State University · USBoston Children's Hospital · USCanada's Michael Smith Genome Sciences Centre · CALevine Cancer Institute · USPenn State Milton S. Hershey Medical Center · USUniversidade Federal do Paraná · BRUniversity of Kansas Medical Center · USVanderbilt University Medical Center · US
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MSPORE in Bladder CancerP50CA221745 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI BAJORIN, DEAN F. · 2018 to 2024
$11.8MProject 3: Modeling tumor evolution and drug response in bladder cancer organoidsP01CA221757 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI ABATE-SHEN, CORY · 2018 to 2022
$8.6MUROLOGY ONCOLOGY RESEARCH TRAINING GRANTT32CA082088 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Brett Stewart Carver · 1999 to 2026
$7.1MTOWARDS PRECISION IMMUNO-ONCOLOGY: UNRAVELING THE GENOMIC DETERMINANTS AND MECHANISMS UNDERLYING IMMUNOTHERAPY EFFICACY AND RESISTANCER35CA232097 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI CHAN, TIMOTHY AN-THY · 2018 to 2024
$7.0MDefining the role of histone H3K4 mono-methyltransferase dysfunction in urothelial carcinomaR01CA265026 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI CHEN, YU · 2022 to 2025
$3.0MDefining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinomaR01CA233899 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI AL-AHMADIE, HIKMAT · 2019 to 2023
$2.0MNCI NIH HHS P01 CA221757NCI NIH HHS P30 CA008748NCI NIH HHS P50 CA221745NCI NIH HHS R01 CA233899NCI NIH HHS R01 CA265026NCI NIH HHS R35 CA232097NCI NIH HHS T32 CA082088
Abstract
Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.
Indexed as
Carcinoma, Squamous CellCarcinoma, Transitional CellUrinary Bladder NeoplasmsBiomarkers, TumorCell LineageHepatocyte Nuclear Factor 3-alphaHumansPhylogenyBiomarkers, TumorFOXA1 protein, humanHepatocyte Nuclear Factor 3-alpha
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