TY  - JOUR
AU  - Sarić, Nemanja
AU  - Selby, Matthew
AU  - Ramaswamy, Vijay
AU  - Kool, Marcel
AU  - Stockinger, Brigitta
AU  - Hogstrand, Christer
AU  - Williamson, Daniel
AU  - Marino, Silvia
AU  - Taylor, Michael D
AU  - Clifford, Steven C
AU  - Basson, M Albert
TI  - The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma.
JO  - Scientific reports
VL  - 10
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DKFZ-2020-00176
SP  - 148
PY  - 2020
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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31924815
DO  - DOI:10.1038/s41598-019-56876-z
UR  - https://inrepo02.dkfz.de/record/153094
ER  -