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The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma
- Source :
- Scientific Reports, Vol 10, Iss 1, Pp 1-16 (2020), Scientific Reports, Saric, N, Selby, M, Ramaswamy, V, Kool, M, Stockinger, B, Hogstrand, C, Williamson, D, Marino, S, Taylor, M D, Clifford, S C & Basson, M A 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
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.
- Subjects :
- Immunology
lcsh:Medicine
Repressor
Article
law.invention
Mice
03 medical and health sciences
0302 clinical medicine
Mediator
Transforming Growth Factor beta
law
medicine
Animals
Hedgehog Proteins
Smad3 Protein
Phosphorylation
Sonic hedgehog
Cancer models
lcsh:Science
Cancer genetics
Cell Proliferation
030304 developmental biology
Medulloblastoma
0303 health sciences
Multidisciplinary
biology
FOS: Clinical medicine
Regeneration (biology)
lcsh:R
Cell Differentiation
medicine.disease
Aryl hydrocarbon receptor
Neural progenitors
In vitro
Gene Expression Regulation, Neoplastic
CNS cancer
Phenotype
Receptors, Aryl Hydrocarbon
030220 oncology & carcinogenesis
Disease Progression
biology.protein
Cancer research
Suppressor
lcsh:Q
Signal Transduction
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....86def68b41116361a72bdeb43f0374c0