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

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 May 14

PMID 35565225

Authors

Doria Filipponi

Marina Pagnuzzi-Boncompagni

Gilles Pages

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

LOXL1-AS1 contributes to metastasis in sonic-hedgehog medulloblastoma by promoting cancer stem-like phenotypes.

Do A, Wu K, Chu S, Giang L, Lin Y, Chang C J Exp Clin Cancer Res. 2024; 43(1):130.

PMID: 38689348 PMC: 11059759. DOI: 10.1186/s13046-024-03057-0.

Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a Relevant Strategy for the Treatment of Paediatric Medulloblastomas.

Penco-Campillo M, Molina C, Piris P, Soufi N, Carre M, Pagnuzzi-Boncompagni M Cells. 2022; 11(23).

PMID: 36497191 PMC: 9738107. DOI: 10.3390/cells11233933.

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