ATOH1 promotes leptomeningeal dissemination and metastasis of sonic hedgehog subgroup medulloblastomas

Katie B. Grausam, Samuel D.R. Dooyema, Laure Bihannic, Hasitha Premathilake, A. Sorana Morrissy, Antoine Forget, Amanda M. Schaefer, Justin H. Gundelach, Slobodan Macura, Diane M. Maher, Xin Wang, Alex H. Heglin, Xijin Ge, Erliang Zeng, Stephanie Puget, Indra Chandrasekar, Kameswaran Surendran, Richard J. Bram, Ulrich Schuller, Michael D. TalyorOlivier Ayrault, Haotian Zhao

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Medulloblastoma arising from the cerebellum is the most like tumor xenografts. Conversely, ATOH1 expression was common pediatric brain malignancy, with leptomeningeal metas-detected consistently in recurrent and metastatic SHH medullo-tases often present at diagnosis and recurrence associated with blastoma. Chromatin immunoprecipitation sequencing and gene poor clinical outcome. In this study, we used mouse medullo-expression profiling identified candidate ATOH1 targets in tumor blastoma models to explore the relationship of tumor pathophys-cells involved in development and tumorigenesis. Among these iology and dysregulated expression of the NOTCH pathway targets specific to metastatic tumors, there was an enrichment in transcription factor ATOH1, which is present in aggressive medul-those implicated in extracellular matrix remodeling activity, cyto-loblastoma subtypes driven by aberrant Sonic Hedgehog/Patched skeletal network and interaction with microenvironment, indicat-(SHH/PTCH) signaling. In experiments with conditional ATOH1 ing a shift in transcriptomic and epigenomic landscapes during mouse mutants crossed to Ptch1þ/ mice, which develop SHH-metastasis. Treatment with bone morphogenetic protein or SHH driven medulloblastoma, animals with Atoh1 transgene expres-pathway inhibitors decreased tumor cell proliferation and supsion developed highly penetrant medulloblastoma at a young age pressed metastatic tumor growth, respectively. Our work reveals a with extensive leptomeningeal disease and metastasis to the spinal dynamic ATOH1-driven molecular cascade underlying medullo-cord and brain, resembling xenografts of human SHH medulloblastoma metastasis that offers possible therapeutic opportunities.

Original languageEnglish (US)
Pages (from-to)3766-3777
Number of pages12
JournalCancer Research
Volume77
Issue number14
DOIs
StatePublished - Jul 15 2017

Fingerprint

Medulloblastoma
Hedgehogs
Neoplasm Metastasis
Neoplasms
Heterografts
Bone Morphogenetic Proteins
Chromatin Immunoprecipitation
Brain
Transgenes
Epigenomics
Cerebellum
Extracellular Matrix
Carcinogenesis
Transcription Factors
Cell Proliferation
Pediatrics
Recurrence
Growth
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Grausam, K. B., Dooyema, S. D. R., Bihannic, L., Premathilake, H., Morrissy, A. S., Forget, A., ... Zhao, H. (2017). ATOH1 promotes leptomeningeal dissemination and metastasis of sonic hedgehog subgroup medulloblastomas. Cancer Research, 77(14), 3766-3777. https://doi.org/10.1158/0008-5472.CAN-16-1836

ATOH1 promotes leptomeningeal dissemination and metastasis of sonic hedgehog subgroup medulloblastomas. / Grausam, Katie B.; Dooyema, Samuel D.R.; Bihannic, Laure; Premathilake, Hasitha; Morrissy, A. Sorana; Forget, Antoine; Schaefer, Amanda M.; Gundelach, Justin H.; Macura, Slobodan; Maher, Diane M.; Wang, Xin; Heglin, Alex H.; Ge, Xijin; Zeng, Erliang; Puget, Stephanie; Chandrasekar, Indra; Surendran, Kameswaran; Bram, Richard J.; Schuller, Ulrich; Talyor, Michael D.; Ayrault, Olivier; Zhao, Haotian.

In: Cancer Research, Vol. 77, No. 14, 15.07.2017, p. 3766-3777.

Research output: Contribution to journalArticle

Grausam, KB, Dooyema, SDR, Bihannic, L, Premathilake, H, Morrissy, AS, Forget, A, Schaefer, AM, Gundelach, JH, Macura, S, Maher, DM, Wang, X, Heglin, AH, Ge, X, Zeng, E, Puget, S, Chandrasekar, I, Surendran, K, Bram, RJ, Schuller, U, Talyor, MD, Ayrault, O & Zhao, H 2017, 'ATOH1 promotes leptomeningeal dissemination and metastasis of sonic hedgehog subgroup medulloblastomas', Cancer Research, vol. 77, no. 14, pp. 3766-3777. https://doi.org/10.1158/0008-5472.CAN-16-1836
Grausam KB, Dooyema SDR, Bihannic L, Premathilake H, Morrissy AS, Forget A et al. ATOH1 promotes leptomeningeal dissemination and metastasis of sonic hedgehog subgroup medulloblastomas. Cancer Research. 2017 Jul 15;77(14):3766-3777. https://doi.org/10.1158/0008-5472.CAN-16-1836
Grausam, Katie B. ; Dooyema, Samuel D.R. ; Bihannic, Laure ; Premathilake, Hasitha ; Morrissy, A. Sorana ; Forget, Antoine ; Schaefer, Amanda M. ; Gundelach, Justin H. ; Macura, Slobodan ; Maher, Diane M. ; Wang, Xin ; Heglin, Alex H. ; Ge, Xijin ; Zeng, Erliang ; Puget, Stephanie ; Chandrasekar, Indra ; Surendran, Kameswaran ; Bram, Richard J. ; Schuller, Ulrich ; Talyor, Michael D. ; Ayrault, Olivier ; Zhao, Haotian. / ATOH1 promotes leptomeningeal dissemination and metastasis of sonic hedgehog subgroup medulloblastomas. In: Cancer Research. 2017 ; Vol. 77, No. 14. pp. 3766-3777.
@article{17d1c09842d9423da2b58db170884aa9,
title = "ATOH1 promotes leptomeningeal dissemination and metastasis of sonic hedgehog subgroup medulloblastomas",
abstract = "Medulloblastoma arising from the cerebellum is the most like tumor xenografts. Conversely, ATOH1 expression was common pediatric brain malignancy, with leptomeningeal metas-detected consistently in recurrent and metastatic SHH medullo-tases often present at diagnosis and recurrence associated with blastoma. Chromatin immunoprecipitation sequencing and gene poor clinical outcome. In this study, we used mouse medullo-expression profiling identified candidate ATOH1 targets in tumor blastoma models to explore the relationship of tumor pathophys-cells involved in development and tumorigenesis. Among these iology and dysregulated expression of the NOTCH pathway targets specific to metastatic tumors, there was an enrichment in transcription factor ATOH1, which is present in aggressive medul-those implicated in extracellular matrix remodeling activity, cyto-loblastoma subtypes driven by aberrant Sonic Hedgehog/Patched skeletal network and interaction with microenvironment, indicat-(SHH/PTCH) signaling. In experiments with conditional ATOH1 ing a shift in transcriptomic and epigenomic landscapes during mouse mutants crossed to Ptch1{\th}/ mice, which develop SHH-metastasis. Treatment with bone morphogenetic protein or SHH driven medulloblastoma, animals with Atoh1 transgene expres-pathway inhibitors decreased tumor cell proliferation and supsion developed highly penetrant medulloblastoma at a young age pressed metastatic tumor growth, respectively. Our work reveals a with extensive leptomeningeal disease and metastasis to the spinal dynamic ATOH1-driven molecular cascade underlying medullo-cord and brain, resembling xenografts of human SHH medulloblastoma metastasis that offers possible therapeutic opportunities.",
author = "Grausam, {Katie B.} and Dooyema, {Samuel D.R.} and Laure Bihannic and Hasitha Premathilake and Morrissy, {A. Sorana} and Antoine Forget and Schaefer, {Amanda M.} and Gundelach, {Justin H.} and Slobodan Macura and Maher, {Diane M.} and Xin Wang and Heglin, {Alex H.} and Xijin Ge and Erliang Zeng and Stephanie Puget and Indra Chandrasekar and Kameswaran Surendran and Bram, {Richard J.} and Ulrich Schuller and Talyor, {Michael D.} and Olivier Ayrault and Haotian Zhao",
year = "2017",
month = "7",
day = "15",
doi = "10.1158/0008-5472.CAN-16-1836",
language = "English (US)",
volume = "77",
pages = "3766--3777",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "14",

}

TY - JOUR

T1 - ATOH1 promotes leptomeningeal dissemination and metastasis of sonic hedgehog subgroup medulloblastomas

AU - Grausam, Katie B.

AU - Dooyema, Samuel D.R.

AU - Bihannic, Laure

AU - Premathilake, Hasitha

AU - Morrissy, A. Sorana

AU - Forget, Antoine

AU - Schaefer, Amanda M.

AU - Gundelach, Justin H.

AU - Macura, Slobodan

AU - Maher, Diane M.

AU - Wang, Xin

AU - Heglin, Alex H.

AU - Ge, Xijin

AU - Zeng, Erliang

AU - Puget, Stephanie

AU - Chandrasekar, Indra

AU - Surendran, Kameswaran

AU - Bram, Richard J.

AU - Schuller, Ulrich

AU - Talyor, Michael D.

AU - Ayrault, Olivier

AU - Zhao, Haotian

PY - 2017/7/15

Y1 - 2017/7/15

N2 - Medulloblastoma arising from the cerebellum is the most like tumor xenografts. Conversely, ATOH1 expression was common pediatric brain malignancy, with leptomeningeal metas-detected consistently in recurrent and metastatic SHH medullo-tases often present at diagnosis and recurrence associated with blastoma. Chromatin immunoprecipitation sequencing and gene poor clinical outcome. In this study, we used mouse medullo-expression profiling identified candidate ATOH1 targets in tumor blastoma models to explore the relationship of tumor pathophys-cells involved in development and tumorigenesis. Among these iology and dysregulated expression of the NOTCH pathway targets specific to metastatic tumors, there was an enrichment in transcription factor ATOH1, which is present in aggressive medul-those implicated in extracellular matrix remodeling activity, cyto-loblastoma subtypes driven by aberrant Sonic Hedgehog/Patched skeletal network and interaction with microenvironment, indicat-(SHH/PTCH) signaling. In experiments with conditional ATOH1 ing a shift in transcriptomic and epigenomic landscapes during mouse mutants crossed to Ptch1þ/ mice, which develop SHH-metastasis. Treatment with bone morphogenetic protein or SHH driven medulloblastoma, animals with Atoh1 transgene expres-pathway inhibitors decreased tumor cell proliferation and supsion developed highly penetrant medulloblastoma at a young age pressed metastatic tumor growth, respectively. Our work reveals a with extensive leptomeningeal disease and metastasis to the spinal dynamic ATOH1-driven molecular cascade underlying medullo-cord and brain, resembling xenografts of human SHH medulloblastoma metastasis that offers possible therapeutic opportunities.

AB - Medulloblastoma arising from the cerebellum is the most like tumor xenografts. Conversely, ATOH1 expression was common pediatric brain malignancy, with leptomeningeal metas-detected consistently in recurrent and metastatic SHH medullo-tases often present at diagnosis and recurrence associated with blastoma. Chromatin immunoprecipitation sequencing and gene poor clinical outcome. In this study, we used mouse medullo-expression profiling identified candidate ATOH1 targets in tumor blastoma models to explore the relationship of tumor pathophys-cells involved in development and tumorigenesis. Among these iology and dysregulated expression of the NOTCH pathway targets specific to metastatic tumors, there was an enrichment in transcription factor ATOH1, which is present in aggressive medul-those implicated in extracellular matrix remodeling activity, cyto-loblastoma subtypes driven by aberrant Sonic Hedgehog/Patched skeletal network and interaction with microenvironment, indicat-(SHH/PTCH) signaling. In experiments with conditional ATOH1 ing a shift in transcriptomic and epigenomic landscapes during mouse mutants crossed to Ptch1þ/ mice, which develop SHH-metastasis. Treatment with bone morphogenetic protein or SHH driven medulloblastoma, animals with Atoh1 transgene expres-pathway inhibitors decreased tumor cell proliferation and supsion developed highly penetrant medulloblastoma at a young age pressed metastatic tumor growth, respectively. Our work reveals a with extensive leptomeningeal disease and metastasis to the spinal dynamic ATOH1-driven molecular cascade underlying medullo-cord and brain, resembling xenografts of human SHH medulloblastoma metastasis that offers possible therapeutic opportunities.

UR - http://www.scopus.com/inward/record.url?scp=85024112982&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85024112982&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-16-1836

DO - 10.1158/0008-5472.CAN-16-1836

M3 - Article

C2 - 28490517

AN - SCOPUS:85024112982

VL - 77

SP - 3766

EP - 3777

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 14

ER -