Sonic Hedgehog (SHH) signaling at primary cilia drives the proliferation and progression of a subset of
medulloblastomas, the most common malignant paediatric
brain tumor. Severe side effects associated with conventional treatments and resistance to targeted
therapies has led to the need for new strategies. SHH signaling is dependent on primary cilia for signal transduction suggesting the potential for cilia destabilizing mechanisms as a therapeutic target. INPP5E is an
inositol polyphosphate 5-phosphatase that hydrolyses
PtdIns(4,5)P2 and more potently, the
phosphoinositide (
PI) 3-kinase product
PtdIns(3,4,5)P3. INPP5E promotes SHH signaling during embryonic development via
PtdIns(4,5)P2 hydrolysis at cilia, that in turn regulates the cilia recruitment of the SHH suppressor GPR161. However, the role INPP5E plays in
cancer is unknown and the contribution of
PI3-kinase signaling to cilia function is little characterized. Here, we reveal INPP5E promotes SHH signaling in SHH
medulloblastoma by negatively regulating a cilia-compartmentalized
PI3-kinase signaling axis that maintains primary cilia on
tumor cells. Conditional deletion of Inpp5e in a murine model of constitutively active Smoothened-driven
medulloblastoma slowed
tumor progression, suppressed cell proliferation, reduced SHH signaling and promoted
tumor cell cilia loss.
PtdIns(3,4,5)P3, its effector pAKT and the target pGSK3β, which when non-phosphorylated promotes cilia assembly/stability, localized to
tumor cell cilia. The number of
PtdIns(3,4,5)P3/pAKT/pGSK3β-positive cilia was increased in cultured Inpp5e-null
tumor cells relative to controls.
PI3-kinase inhibition or expression of wild-type, but not catalytically inactive HA-INPP5E partially rescued cilia loss in Inpp5e-null
tumor cells in vitro. INPP5E
mRNA and copy number were reduced in human SHH
medulloblastoma compared to other molecular subtypes and consistent with the murine model, reduced INPP5E was associated with improved overall survival. Therefore our study identifies a compartmentalized
PtdIns(3,4,5)P3/AKT/GSK3β signaling axis at cilia in SHH-dependent
medulloblastoma that is regulated by INPP5E to maintain
tumor cell cilia, promote SHH signaling and thereby
medulloblastoma progression.