%0 Journal Article
%A Sarić, Nemanja
%A Selby, Matthew
%A Ramaswamy, Vijay
%A Kool, Marcel
%A Stockinger, Brigitta
%A Hogstrand, Christer
%A Williamson, Daniel
%A Marino, Silvia
%A Taylor, Michael D
%A Clifford, Steven C
%A Basson, M Albert
%T The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma.
%J Scientific reports
%V 10
%N 1
%@ 2045-2322
%C [London]
%I Macmillan Publishers Limited, part of Springer Nature
%M DKFZ-2020-00176
%P 148
%D 2020
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:31924815
%R 10.1038/s41598-019-56876-z
%U https://inrepo02.dkfz.de/record/153094