Cell Reports
(May 2024)
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
Affiliations
Sangkyou Lee
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jolanta Bondaruk
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Yishan Wang
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Huiqin Chen
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
June Goo Lee
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Tadeusz Majewski
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Rachel D. Mullen
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
David Cogdell
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jiansong Chen
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Ziqiao Wang
Department of Biostatistics, Johns Hopkins University, Baltimore, MD 21218, USA
Hui Yao
Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Pawel Kus
Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland
Joon Jeong
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Ilkyun Lee
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Woonyoung Choi
Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD 21218, USA
Neema Navai
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Charles Guo
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Colin Dinney
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Keith Baggerly
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Cathy Mendelsohn
Department of Urology, Genetics & Development and Pathology, Columbia University, New York, NY 10032, USA
David McConkey
Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD 21218, USA
Richard R. Behringer
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Marek Kimmel
Department of Statistics, Rice University, Houston, TX 77005, USA
Peng Wei
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Bogdan Czerniak
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Corresponding author
Journal volume & issue
Vol. 43,
no. 5
Abstract
Read online
Summary: 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.
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