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

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

Authors:	Warrick, J. I.; Hu, W.; Yamashita, H.; Walter, V.; Shuman, L.; Craig, J. M.; Gellert, L. L.; Castro, M. A. A.; Robertson, A. G.; Kuo, F.; Ostrovnaya, I.; Sarungbam, J.; Chen, Y. B.; Gopalan, A.; Sirintrapun, S. J.; Fine, S. W.; Tickoo, S. K.; Kim, K.; Thomas, J.; Karan, N.; Gao, S. P.; Clinton, T. N.; Lenis, A. T.; Chan, T. A.; Chen, Z.; Rao, M.; Hollman, T. J.; Li, Y.; Socci, N. D.; Chavan, S.; Viale, A.; Mohibullah, N.; Bochner, B. H.; Pietzak, E. J.; Teo, M. Y.; Iyer, G.; Rosenberg, J. E.; Bajorin, D. F.; Kaag, M.; Merrill, S. B.; Joshi, M.; Adam, R.; Taylor, J. A. 3rd; Clark, P. E.; Raman, J. D.; Reuter, V. E.; Chen, Y.; Funt, S. A.; Solit, D. B.; DeGraff, D. J.; Al-Ahmadie, H. A.
Article Title:	FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation
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. © 2022, The Author(s).
Keywords:	genetics; squamous cell carcinoma; carcinoma, squamous cell; metabolism; hepatocyte nuclear factor 3alpha; gene expression; pathology; tumor marker; bladder tumor; urinary bladder neoplasms; histology; immune response; biomarker; genomics; carcinoma, transitional cell; transitional cell carcinoma; differentiation; phylogeny; heterogeneity; plasticity; hepatocyte nuclear factor 3-alpha; cancer; humans; human; biomarkers, tumor; foxa1 protein, human
Journal Title:	Nature Communications
Volume:	13
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2022-11-02
Start Page:	6575
Language:	English
DOI:	10.1038/s41467-022-34251-3
PUBMED:	36323682
PROVIDER:	scopus
PMCID:	PMC9630410
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85141130680&doi=10.1038%2fs41467-022-34251-3&partnerID=40&md5=841326297a2831de56e6b585431f55d7
Notes:	PDF misspells the author: Ziyu Chen's first name; PDS misformats the author: Karan Nagar's name; PDF shortens the author: Gopakumar Iye's first name to: Gopa -- Erratum published at DOI: 10.1038/s41467-022-35644-0 -- Source: Scopus