Inhibiting ALK2/ALK3 Signaling to Differentiate and Chemo-Sensitize Medulloblastoma

Simple Summary Many cancers re-emerge after treatment, despite the sensitivity of the bulk of tumor cells to treatments. This observation has led to the 'cancer stem cell' (CSCs) hypothesis, stating that a subpopulation of cancer cells survive therapy and lead to tumor relapse. However, the lack of universal markers to target CSCs is the main constraint to fully eradicate the CSC pool. Differentiation therapy (DT) might in principle suppress tumorigenesis through conversion of undifferentiated cancer cells of high malignancy into differentiated cells of low tumorigenic potential. Here, we provide evidence that CSCs of medulloblastoma can be forced to resume their differentiation potential by inhibiting the BMP4-ALK2/3 axis, providing a new entry point for medulloblastoma treatment. Background: Medulloblastoma (MB) is a malignant pediatric brain tumor, and it represents the leading cause of death related to cancer in childhood. New perspectives for therapeutic development have emerged with the identification of cancer stem cells (CSCs) displaying tumor initiating capability and chemoresistance. However, the mechanisms responsible for CSCs maintenance are poorly understood. The lack of a universal marker signature represents the main constraints to identify and isolate CSCs within the tumor. Methods: To identify signaling pathways promoting CSC maintenance in MB, we combined tumorsphere assays with targeted neurogenesis PCR pathway arrays. Results: We showed a consistent induction of signaling pathways regulating pluripotency of CSCs in all the screened MB cells. BMP4 signaling was consistently enriched in all tumorsphere(s) independently of their specific stem-cell marker profile. The octamer-binding transcription factor 4 (OCT4), an important regulator of embryonic pluripotency, enhanced CSC maintenance in MBs by inducing the BMP4 signaling pathway. Consistently, inhibition of BMP4 signaling with LDN-193189 reduced stem-cell traits and promoted cell differentiation. Conclusions: Our work suggests that interfering with the BMP4 signaling pathway impaired the maintenance of the CSC pool by promoting cell differentiation. Hence, differentiation therapy might represent an innovative therapeutic to improve the current standard of care in MB patients.