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

• DOI: 10.1038/s41467-022-34251-3
• Publication Date: 2022-11-02T20:29:15Z
• Authors: 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. Si...; Samson W. Fine; Satish K. Tickoo; Kwanghee Kim; Jasmine Thomas; Nagar Karan; Sizhi Paul Gao; Timothy N. Clinton; Andrew T. Lenis; Timothy A. Chan; Ziyu 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. Rosen...; 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
• Keywords: Lineage (genetic)

Abstract Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed divergent histomorphology, most commonly squamous differentiation. To define biologic basis for and clinical significance this morphologic heterogeneity, here we perform integrated genomic analyses mixed histology cancers separable We find that differentiation is a marker intratumoral immunologic heterogeneity in patients cancer biomarker intrinsic immunotherapy resistance. Phylogenetic analysis confirms all cases are derived common shared precursor. Despite presence marked between co-existent differentiated regions, no recurrent alteration exclusive morphologies identified. Rather, associated loss expression FOXA1 , GATA3 PPARG transcription factors critical maintenance cell identity. Of significance, PD-L1 coordinately dysregulated via exhibiting pre-treatment significantly less likely respond immune checkpoint inhibitors.