Urothelial-to-Neural Plasticity Drives Progression to Small Cell Bladder Cancer

Guoliang Yang; Jolanta Bondaruk; David Cogdell; Ziqiao Wang; Sangkyou Lee; June Goo Lee; Shizhen Zhang; Woonyoung Choi; Yan Wang; Yu Liang; Gang Wang; Ying Wang; Hui Yao; Vipulkumar Dadhania; Jianjun Gao; Christopher Logothetis; Arlene Siefker-Radtke; Ashish Kamat; Colin Dinney; Dan Theodorescu; Marek Kimmel; Peng Wei; Charles C Guo; John N Weinstein; David J McConkey; Bogdan Czerniak

doi:10.1016/j.isci.2020.101201

Urothelial-to-Neural Plasticity Drives Progression to Small Cell Bladder Cancer

iScience. 2020 Jun 26;23(6):101201. doi: 10.1016/j.isci.2020.101201. Epub 2020 May 27.

Authors

Guoliang Yang¹, Jolanta Bondaruk¹, David Cogdell¹, Ziqiao Wang², Sangkyou Lee¹, June Goo Lee¹, Shizhen Zhang¹, Woonyoung Choi³, Yan Wang¹, Yu Liang¹, Gang Wang¹, Ying Wang², Hui Yao⁴, Vipulkumar Dadhania¹, Jianjun Gao⁵, Christopher Logothetis⁵, Arlene Siefker-Radtke⁵, Ashish Kamat⁶, Colin Dinney⁶, Dan Theodorescu⁷, Marek Kimmel⁸, Peng Wei², Charles C Guo⁹, John N Weinstein⁴, David J McConkey³, Bogdan Czerniak¹⁰

Affiliations

¹ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, Los Angeles, CA, USA.
⁸ Department of Statistics, Rice University, Houston, TX, USA.
⁹ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ccguo@mdanderson.org.
¹⁰ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: bczernia@mdanderson.org.

Abstract

We report a comprehensive molecular analysis of 34 cases of small cell carcinoma (SCC) and 84 cases of conventional urothelial carcinoma (UC), with The Cancer Genome Atlas cohort of 408 conventional UC bladder cancers used as the reference. SCCs showed mutational landscapes characterized by nearly uniform inactivation of TP53 and were dominated by Sanger mutation signature 3 associated with loss of BRCA1/2 function. SCCs were characterized by downregulation of luminal and basal markers and were referred to as double-negative. Transcriptome analyses indicated that SCCs displayed lineage plasticity driven by a urothelial-to-neural phenotypic switch with a dysregulated epithelial-to-mesenchymal transition network. SCCs were depleted of immune cells, and expressed high levels of the immune checkpoint receptor, adenosine receptor A2A (ADORA2A), which is a potent inhibitor of immune infiltration. Our observations have important implications for the prognostication and development of more effective therapies for this lethal bladder cancer variant.

Keywords: Biological Sciences; Cancer; Cancer Systems Biology; Genomics; Transcriptomics.

Grants and funding

P30 CA016672/CA/NCI NIH HHS/United States