Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis

Sangkyou Lee; Jolanta Bondaruk; Yishan Wang; Huiqin Chen; June Goo Lee; Tadeusz Majewski; Rachel D Mullen; David Cogdell; Jiansong Chen; Ziqiao Wang; Hui Yao; Pawel Kus; Joon Jeong; Ilkyun Lee; Woonyoung Choi; Neema Navai; Charles Guo; Colin Dinney; Keith Baggerly; Cathy Mendelsohn; David McConkey; Richard R Behringer; Marek Kimmel; Peng Wei; Bogdan Czerniak

doi:10.1016/j.celrep.2024.114146

Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis

Cell Rep. 2024 Apr 25;43(5):114146. doi: 10.1016/j.celrep.2024.114146. Online ahead of print.

Authors

Sangkyou Lee¹, Jolanta Bondaruk¹, Yishan Wang², Huiqin Chen², June Goo Lee¹, Tadeusz Majewski¹, Rachel D Mullen³, David Cogdell⁴, Jiansong Chen², Ziqiao Wang⁵, Hui Yao⁶, Pawel Kus⁷, Joon Jeong¹, Ilkyun Lee¹, Woonyoung Choi⁸, Neema Navai⁹, Charles Guo¹, Colin Dinney⁹, Keith Baggerly², Cathy Mendelsohn¹⁰, David McConkey⁸, Richard R Behringer³, Marek Kimmel¹¹, Peng Wei², Bogdan Czerniak¹²

Affiliations

¹ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ Department of Biostatistics, Johns Hopkins University, Baltimore, MD 21218, USA.
⁶ Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland.
⁸ Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD 21218, USA.
⁹ Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Urology, Genetics & Development and Pathology, Columbia University, New York, NY 10032, USA.
¹¹ Department of Statistics, Rice University, Houston, TX 77005, USA.
¹² Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: bczernia@mdanderson.org.

PMID: 38676926
DOI: 10.1016/j.celrep.2024.114146

Abstract

We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term "forerunner" genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two of these genes, LPAR6 and CAB39L, are preferentially downregulated in the luminal and basal subtypes of bladder cancer, respectively. Their loss of function dysregulates urothelial differentiation, sensitizing the urothelium to N-butyl-N-(4-hydroxybutyl)nitrosamine-induced cancers, which recapitulate the luminal and basal subtypes of human bladder cancer.

Keywords: CP: Cancer; bladder cancer; field carcinogenesis; field effects; forerunner genes; mucosal microenvironment; urothelial differentiation.