Loss of LPAR6 and CAB39L Dysregulates the Basal-To-Luminal Urothelial Differentiation Program, Contributing to Bladder Carcinogenesis

Authors

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

Publication Date

5-28-2024

Journal

Cell Reports

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

Aged, Aged, 80 and over, Animals, Female, Humans, Male, Mice, Middle Aged, Carcinogenesis, Cell Differentiation, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Receptors, Lysophosphatidic Acid, Urinary Bladder Neoplasms, Urothelium

Comments

Supplementary Materials

PMID: 38676926