FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation

Joshua I. Warrick, Wenhuo Hu, Hironobu Yamashita, Vonn Walter, Lauren Shuman, Jenna M. Craig, Lan L. Gellert, Mauro A.A. Castro, A. Gordon Robertson, Fengshen Kuo, Irina Ostrovnaya, Judy Sarungbam, Ying bei Chen, Anuradha Gopalan, Sahussapont J. Sirintrapun, Samson W. Fine, Satish K. Tickoo, Kwanghee Kim, Jasmine Thomas, Nagar KaranSizhi Paul Gao, Timothy N. Clinton, Andrew T. Lenis, Timothy A. Chan, Zhiyu Chen, Manisha Rao, Travis J. Hollman, Yanyun Li, Nicholas D. Socci, Shweta Chavan, Agnes Viale, Neeman Mohibullah, Bernard H. Bochner, Eugene J. Pietzak, Min Yuen Teo, Gopa Iyer, Jonathan E. Rosenberg, Dean F. Bajorin, Matthew Kaag, Suzanne B. Merrill, Monika Joshi, Rosalyn Adam, John A. Taylor, Peter E. Clark, Jay D. Raman, Victor E. Reuter, Yu Chen, Samuel A. Funt, David B. Solit, David J. DeGraff, Hikmat A. Al-Ahmadie

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish (US)
Article number6575
JournalNature communications
Issue number1
StatePublished - Dec 2022

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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