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

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 MendelsohnDavid McConkey, Richard R. Behringer, Marek Kimmel, Peng Wei, Bogdan Czerniak

Department of Surgery

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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.

Original language	English
Article number	114146
Journal	Cell Reports
Volume	43
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2024.114146
Publication status	Published - 2024 May 28

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2024.114146

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Lee, S., Bondaruk, J., Wang, Y., Chen, H., Lee, J. G., Majewski, T., Mullen, R. D., Cogdell, D., Chen, J., Wang, Z., Yao, H., Kus, P., Jeong, J., Lee, I., Choi, W., Navai, N., Guo, C., Dinney, C., Baggerly, K., ... Czerniak, B. (2024). Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis. Cell Reports, 43(5), Article 114146. https://doi.org/10.1016/j.celrep.2024.114146

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = may,

day = "28",

doi = "10.1016/j.celrep.2024.114146",

language = "English",

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Lee, S, Bondaruk, J, Wang, Y, Chen, H, Lee, JG, Majewski, T, Mullen, RD, Cogdell, D, Chen, J, Wang, Z, Yao, H, Kus, P, Jeong, J, Lee, I, Choi, W, Navai, N, Guo, C, Dinney, C, Baggerly, K, Mendelsohn, C, McConkey, D, Behringer, RR, Kimmel, M, Wei, P & Czerniak, B 2024, 'Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis', Cell Reports, vol. 43, no. 5, 114146. https://doi.org/10.1016/j.celrep.2024.114146

TY - JOUR

T1 - Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis

AU - Lee, Sangkyou

AU - Bondaruk, Jolanta

AU - Wang, Yishan

AU - Chen, Huiqin

AU - Lee, June Goo

AU - Majewski, Tadeusz

AU - Mullen, Rachel D.

AU - Cogdell, David

AU - Chen, Jiansong

AU - Wang, Ziqiao

AU - Yao, Hui

AU - Kus, Pawel

AU - Jeong, Joon

AU - Lee, Ilkyun

AU - Choi, Woonyoung

AU - Navai, Neema

AU - Guo, Charles

AU - Dinney, Colin

AU - Baggerly, Keith

AU - Mendelsohn, Cathy

AU - McConkey, David

AU - Behringer, Richard R.

AU - Kimmel, Marek

AU - Wei, Peng

AU - Czerniak, Bogdan

PY - 2024/5/28

Y1 - 2024/5/28

N2 - 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.

AB - 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.

KW - CP: Cancer

KW - bladder cancer

KW - field carcinogenesis

KW - field effects

KW - forerunner genes

KW - mucosal microenvironment

KW - urothelial differentiation

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U2 - 10.1016/j.celrep.2024.114146

DO - 10.1016/j.celrep.2024.114146

M3 - Article

C2 - 38676926

AN - SCOPUS:85190989834

SN - 2211-1247

VL - 43

JO - Cell Reports

JF - Cell Reports

IS - 5

M1 - 114146

ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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