Hypermethylation of FOXA1 and allelic loss of PTEN drive squamous differentiation and promote heterogeneity in bladder cancer

Vasty Osei-Amponsa, Jenna M. Buckwalter, Lauren Shuman, Zongyu Zheng, Hironobu Yamashita, Vonn Walter, Thomas Wildermuth, Justine Ellis-Mohl, Chang Liu, Joshua I. Warrick, Lisa M. Shantz, Robert P. Feehan, Hikmat Al-Ahmadie, Cathy Mendelsohn, Jay D. Raman, Klaus H. Kaestner, Xue Ru Wu, David J. DeGraff

Research output: Contribution to journalArticle

Abstract

Intratumoral heterogeneity in bladder cancer is a barrier to accurate molecular sub-classification and treatment efficacy. However, individual cellular and mechanistic contributions to tumor heterogeneity are controversial. We examined potential mechanisms of FOXA1 and PTEN inactivation in bladder cancer and their contribution to tumor heterogeneity. These analyses were complemented with inactivation of FOXA1 and PTEN in intermediate and luminal mouse urothelium. We show inactivation and reduced expression of FOXA1 and PTEN is prevalent in human disease, where PTEN and FOXA1 are downregulated by allelic loss and site-specific DNA hypermethylation, respectively. Conditional inactivation of both Foxa1 and Pten in intermediate/luminal cells in mice results in development of bladder cancer exhibiting squamous features as well as enhanced sensitivity to a bladder-specific carcinogen. In addition, FOXA1 is hypermethylated in basal bladder cancer cell lines, and this is reversed by treatment with DNA methyltransferase inhibitors. By integrating human correlative and in vivo studies, we define a critical role for PTEN loss and epigenetic silencing of FOXA1 in heterogeneous human disease and show genetic targeting of luminal/intermediate cells in mice drives squamous differentiation.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Jan 1 2019

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Loss of Heterozygosity
Urinary Bladder Neoplasms
Urothelium
Inborn Genetic Diseases
DNA
Methyltransferases
Epigenomics
Carcinogens
Neoplasms
Urinary Bladder
Down-Regulation
Cell Line

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Osei-Amponsa, Vasty ; Buckwalter, Jenna M. ; Shuman, Lauren ; Zheng, Zongyu ; Yamashita, Hironobu ; Walter, Vonn ; Wildermuth, Thomas ; Ellis-Mohl, Justine ; Liu, Chang ; Warrick, Joshua I. ; Shantz, Lisa M. ; Feehan, Robert P. ; Al-Ahmadie, Hikmat ; Mendelsohn, Cathy ; Raman, Jay D. ; Kaestner, Klaus H. ; Wu, Xue Ru ; DeGraff, David J. / Hypermethylation of FOXA1 and allelic loss of PTEN drive squamous differentiation and promote heterogeneity in bladder cancer. In: Oncogene. 2019.
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abstract = "Intratumoral heterogeneity in bladder cancer is a barrier to accurate molecular sub-classification and treatment efficacy. However, individual cellular and mechanistic contributions to tumor heterogeneity are controversial. We examined potential mechanisms of FOXA1 and PTEN inactivation in bladder cancer and their contribution to tumor heterogeneity. These analyses were complemented with inactivation of FOXA1 and PTEN in intermediate and luminal mouse urothelium. We show inactivation and reduced expression of FOXA1 and PTEN is prevalent in human disease, where PTEN and FOXA1 are downregulated by allelic loss and site-specific DNA hypermethylation, respectively. Conditional inactivation of both Foxa1 and Pten in intermediate/luminal cells in mice results in development of bladder cancer exhibiting squamous features as well as enhanced sensitivity to a bladder-specific carcinogen. In addition, FOXA1 is hypermethylated in basal bladder cancer cell lines, and this is reversed by treatment with DNA methyltransferase inhibitors. By integrating human correlative and in vivo studies, we define a critical role for PTEN loss and epigenetic silencing of FOXA1 in heterogeneous human disease and show genetic targeting of luminal/intermediate cells in mice drives squamous differentiation.",
author = "Vasty Osei-Amponsa and Buckwalter, {Jenna M.} and Lauren Shuman and Zongyu Zheng and Hironobu Yamashita and Vonn Walter and Thomas Wildermuth and Justine Ellis-Mohl and Chang Liu and Warrick, {Joshua I.} and Shantz, {Lisa M.} and Feehan, {Robert P.} and Hikmat Al-Ahmadie and Cathy Mendelsohn and Raman, {Jay D.} and Kaestner, {Klaus H.} and Wu, {Xue Ru} and DeGraff, {David J.}",
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Osei-Amponsa, V, Buckwalter, JM, Shuman, L, Zheng, Z, Yamashita, H, Walter, V, Wildermuth, T, Ellis-Mohl, J, Liu, C, Warrick, JI, Shantz, LM, Feehan, RP, Al-Ahmadie, H, Mendelsohn, C, Raman, JD, Kaestner, KH, Wu, XR & DeGraff, DJ 2019, 'Hypermethylation of FOXA1 and allelic loss of PTEN drive squamous differentiation and promote heterogeneity in bladder cancer', Oncogene. https://doi.org/10.1038/s41388-019-1063-4

Hypermethylation of FOXA1 and allelic loss of PTEN drive squamous differentiation and promote heterogeneity in bladder cancer. / Osei-Amponsa, Vasty; Buckwalter, Jenna M.; Shuman, Lauren; Zheng, Zongyu; Yamashita, Hironobu; Walter, Vonn; Wildermuth, Thomas; Ellis-Mohl, Justine; Liu, Chang; Warrick, Joshua I.; Shantz, Lisa M.; Feehan, Robert P.; Al-Ahmadie, Hikmat; Mendelsohn, Cathy; Raman, Jay D.; Kaestner, Klaus H.; Wu, Xue Ru; DeGraff, David J.

In: Oncogene, 01.01.2019.

Research output: Contribution to journalArticle

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T1 - Hypermethylation of FOXA1 and allelic loss of PTEN drive squamous differentiation and promote heterogeneity in bladder cancer

AU - Osei-Amponsa, Vasty

AU - Buckwalter, Jenna M.

AU - Shuman, Lauren

AU - Zheng, Zongyu

AU - Yamashita, Hironobu

AU - Walter, Vonn

AU - Wildermuth, Thomas

AU - Ellis-Mohl, Justine

AU - Liu, Chang

AU - Warrick, Joshua I.

AU - Shantz, Lisa M.

AU - Feehan, Robert P.

AU - Al-Ahmadie, Hikmat

AU - Mendelsohn, Cathy

AU - Raman, Jay D.

AU - Kaestner, Klaus H.

AU - Wu, Xue Ru

AU - DeGraff, David J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Intratumoral heterogeneity in bladder cancer is a barrier to accurate molecular sub-classification and treatment efficacy. However, individual cellular and mechanistic contributions to tumor heterogeneity are controversial. We examined potential mechanisms of FOXA1 and PTEN inactivation in bladder cancer and their contribution to tumor heterogeneity. These analyses were complemented with inactivation of FOXA1 and PTEN in intermediate and luminal mouse urothelium. We show inactivation and reduced expression of FOXA1 and PTEN is prevalent in human disease, where PTEN and FOXA1 are downregulated by allelic loss and site-specific DNA hypermethylation, respectively. Conditional inactivation of both Foxa1 and Pten in intermediate/luminal cells in mice results in development of bladder cancer exhibiting squamous features as well as enhanced sensitivity to a bladder-specific carcinogen. In addition, FOXA1 is hypermethylated in basal bladder cancer cell lines, and this is reversed by treatment with DNA methyltransferase inhibitors. By integrating human correlative and in vivo studies, we define a critical role for PTEN loss and epigenetic silencing of FOXA1 in heterogeneous human disease and show genetic targeting of luminal/intermediate cells in mice drives squamous differentiation.

AB - Intratumoral heterogeneity in bladder cancer is a barrier to accurate molecular sub-classification and treatment efficacy. However, individual cellular and mechanistic contributions to tumor heterogeneity are controversial. We examined potential mechanisms of FOXA1 and PTEN inactivation in bladder cancer and their contribution to tumor heterogeneity. These analyses were complemented with inactivation of FOXA1 and PTEN in intermediate and luminal mouse urothelium. We show inactivation and reduced expression of FOXA1 and PTEN is prevalent in human disease, where PTEN and FOXA1 are downregulated by allelic loss and site-specific DNA hypermethylation, respectively. Conditional inactivation of both Foxa1 and Pten in intermediate/luminal cells in mice results in development of bladder cancer exhibiting squamous features as well as enhanced sensitivity to a bladder-specific carcinogen. In addition, FOXA1 is hypermethylated in basal bladder cancer cell lines, and this is reversed by treatment with DNA methyltransferase inhibitors. By integrating human correlative and in vivo studies, we define a critical role for PTEN loss and epigenetic silencing of FOXA1 in heterogeneous human disease and show genetic targeting of luminal/intermediate cells in mice drives squamous differentiation.

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