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

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
p. 114146

Abstract

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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.

CP: Cancer

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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