FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation
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Published:2022-11-02
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Warrick Joshua I.ORCID, Hu WenhuoORCID, Yamashita Hironobu, Walter VonnORCID, Shuman LaurenORCID, Craig Jenna M., Gellert Lan L., Castro Mauro A. A., Robertson A. Gordon, Kuo FengshenORCID, Ostrovnaya Irina, Sarungbam Judy, Chen Ying-beiORCID, Gopalan Anuradha, Sirintrapun Sahussapont J., Fine Samson W.ORCID, Tickoo Satish K.ORCID, Kim KwangheeORCID, Thomas Jasmine, Karan Nagar, Gao Sizhi Paul, Clinton Timothy N.ORCID, Lenis Andrew T.ORCID, Chan Timothy A.ORCID, Chen ZiyuORCID, Rao Manisha, Hollman Travis J.ORCID, Li Yanyun, Socci Nicholas D., Chavan Shweta, Viale Agnes, Mohibullah Neeman, Bochner Bernard H., Pietzak Eugene J., Teo Min YuenORCID, Iyer GopaORCID, Rosenberg Jonathan E., Bajorin Dean F.ORCID, Kaag Matthew, Merrill Suzanne B., Joshi Monika, Adam RosalynORCID, Taylor John A., Clark Peter E., Raman Jay D., Reuter Victor E., Chen YuORCID, Funt Samuel A.ORCID, Solit David B.ORCID, DeGraff David J.ORCID, Al-Ahmadie Hikmat A.ORCID
Abstract
AbstractCancers 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.
Funder
U.S. Department of Defense American Cancer Society U.S. Department of Health & Human Services | NIH | National Cancer Institute The Albert Institute for Bladder Cancer Care and Research, Parker Institute for Cancer Immunotherapy, Cycle for Survival, the Mark Foundation.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference77 articles.
1. Loehrer, P. J. Sr. et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J. Clin. Oncol. 10, 1066–1073 (1992). 2. von der Maase, H. et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J. Clin. Oncol. 23, 4602–4608 (2005). 3. De Santis, M. et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J. Clin. Oncol. 30, 191–199 (2012). 4. Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016). 5. Zibelman, M., Ramamurthy, C. & Plimack, E. R. Emerging role of immunotherapy in urothelial carcinoma-Advanced disease. Urol. Oncol. 34, 538–547 (2016).
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