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The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma

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The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma. / Saric, Nemanja; Selby, Matthew; Ramaswamy, Vijay; Kool, Marcel; Stockinger, Brigitta ; Hogstrand, Jan Lennart Christer; Williamson, Daniel; Marino, Silvia; Taylor, Michael D. ; Clifford, Steven C.; Basson, Michiel Albertus.

In: Scientific Reports, Vol. 10, No. 1, 148, 01.12.2020.

Research output: Contribution to journalArticle

Harvard

Saric, N, Selby, M, Ramaswamy, V, Kool, M, Stockinger, B, Hogstrand, JLC, Williamson, D, Marino, S, Taylor, MD, Clifford, SC & Basson, MA 2020, 'The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma', Scientific Reports, vol. 10, no. 1, 148. https://doi.org/10.1038/s41598-019-56876-z

APA

Saric, N., Selby, M., Ramaswamy, V., Kool, M., Stockinger, B., Hogstrand, J. L. C., ... Basson, M. A. (2020). The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma. Scientific Reports, 10(1), [148]. https://doi.org/10.1038/s41598-019-56876-z

Vancouver

Saric N, Selby M, Ramaswamy V, Kool M, Stockinger B, Hogstrand JLC et al. The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma. Scientific Reports. 2020 Dec 1;10(1). 148. https://doi.org/10.1038/s41598-019-56876-z

Author

Saric, Nemanja ; Selby, Matthew ; Ramaswamy, Vijay ; Kool, Marcel ; Stockinger, Brigitta ; Hogstrand, Jan Lennart Christer ; Williamson, Daniel ; Marino, Silvia ; Taylor, Michael D. ; Clifford, Steven C. ; Basson, Michiel Albertus. / The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma. In: Scientific Reports. 2020 ; Vol. 10, No. 1.

Bibtex Download

@article{69c1bbbb88254f369c372c143cddfd92,
title = "The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma",
abstract = "Sonic Hedgehog (SHH) medulloblastomas are brain tumours that arise in the posterior fossa. Cancer-propagating cells (CPCs) provide a reservoir of cells capable of tumour regeneration and relapse post-treatment. Understanding and targeting the mechanisms by which CPCs are maintained and expanded in SHH medulloblastoma could present novel therapeutic opportunities. We identified the aryl hydrocarbon receptor (AHR) pathway as a potent tumour suppressor in a SHH medulloblastoma mouse model. Ahr-deficient tumours and CPCs grown in vitro, showed elevated activation of the TGFβ mediator, SMAD3. Pharmacological inhibition of the TGFβ/SMAD3 signalling axis was sufficient to inhibit the proliferation and promote the differentiation of Ahr-deficient CPCs. Human SHH medulloblastomas with high expression of the AHR repressor (AHRR) exhibited a significantly worse prognosis compared to AHRRlow tumours in two independent patient cohorts. Together, these findings suggest that reduced AHR pathway activity promotes SHH medulloblastoma progression, consistent with a tumour suppressive role for AHR. We propose that TGFβ/SMAD3 inhibition may represent an actionable therapeutic approach for a subset of aggressive SHH medulloblastomas characterised by reduced AHR pathway activity.",
author = "Nemanja Saric and Matthew Selby and Vijay Ramaswamy and Marcel Kool and Brigitta Stockinger and Hogstrand, {Jan Lennart Christer} and Daniel Williamson and Silvia Marino and Taylor, {Michael D.} and Clifford, {Steven C.} and Basson, {Michiel Albertus}",
year = "2020",
month = "1",
day = "10",
doi = "10.1038/s41598-019-56876-z",
language = "English",
volume = "10",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma

AU - Saric, Nemanja

AU - Selby, Matthew

AU - Ramaswamy, Vijay

AU - Kool, Marcel

AU - Stockinger, Brigitta

AU - Hogstrand, Jan Lennart Christer

AU - Williamson, Daniel

AU - Marino, Silvia

AU - Taylor, Michael D.

AU - Clifford, Steven C.

AU - Basson, Michiel Albertus

PY - 2020/1/10

Y1 - 2020/1/10

N2 - Sonic Hedgehog (SHH) medulloblastomas are brain tumours that arise in the posterior fossa. Cancer-propagating cells (CPCs) provide a reservoir of cells capable of tumour regeneration and relapse post-treatment. Understanding and targeting the mechanisms by which CPCs are maintained and expanded in SHH medulloblastoma could present novel therapeutic opportunities. We identified the aryl hydrocarbon receptor (AHR) pathway as a potent tumour suppressor in a SHH medulloblastoma mouse model. Ahr-deficient tumours and CPCs grown in vitro, showed elevated activation of the TGFβ mediator, SMAD3. Pharmacological inhibition of the TGFβ/SMAD3 signalling axis was sufficient to inhibit the proliferation and promote the differentiation of Ahr-deficient CPCs. Human SHH medulloblastomas with high expression of the AHR repressor (AHRR) exhibited a significantly worse prognosis compared to AHRRlow tumours in two independent patient cohorts. Together, these findings suggest that reduced AHR pathway activity promotes SHH medulloblastoma progression, consistent with a tumour suppressive role for AHR. We propose that TGFβ/SMAD3 inhibition may represent an actionable therapeutic approach for a subset of aggressive SHH medulloblastomas characterised by reduced AHR pathway activity.

AB - Sonic Hedgehog (SHH) medulloblastomas are brain tumours that arise in the posterior fossa. Cancer-propagating cells (CPCs) provide a reservoir of cells capable of tumour regeneration and relapse post-treatment. Understanding and targeting the mechanisms by which CPCs are maintained and expanded in SHH medulloblastoma could present novel therapeutic opportunities. We identified the aryl hydrocarbon receptor (AHR) pathway as a potent tumour suppressor in a SHH medulloblastoma mouse model. Ahr-deficient tumours and CPCs grown in vitro, showed elevated activation of the TGFβ mediator, SMAD3. Pharmacological inhibition of the TGFβ/SMAD3 signalling axis was sufficient to inhibit the proliferation and promote the differentiation of Ahr-deficient CPCs. Human SHH medulloblastomas with high expression of the AHR repressor (AHRR) exhibited a significantly worse prognosis compared to AHRRlow tumours in two independent patient cohorts. Together, these findings suggest that reduced AHR pathway activity promotes SHH medulloblastoma progression, consistent with a tumour suppressive role for AHR. We propose that TGFβ/SMAD3 inhibition may represent an actionable therapeutic approach for a subset of aggressive SHH medulloblastomas characterised by reduced AHR pathway activity.

UR - http://www.scopus.com/inward/record.url?scp=85077700022&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-56876-z

DO - 10.1038/s41598-019-56876-z

M3 - Article

VL - 10

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 148

ER -

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