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

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, Christer

AU - Williamson, Daniel

AU - Marino, Silvia

AU - Taylor, Michael D.

AU - Clifford, Steven C.

AU - Basson, M. Albert

PY - 2020/1

Y1 - 2020/1

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

SN - 2045-2322

VL - 10

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 148

ER -