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Of travelling homeoproteins and medulloblastomas

Oncogene volume 44, pages 3043–3051 (2025)Cite this article

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Abstract

Medulloblastomas are the most common solid paediatric cancers. Their prognosis largely depends on tumour subtype and expression level of transcription factor such as Orthodenticle homeobox 2 (OTX2). OTX2 is an homeoprotein that maintains stemness and initiates oncogenic pathways. Additionally, as many other homeoproteins, OTX2 is able to travel between cells and to modify the transcriptional activity of recipient ones. After identifying travelling proteins in in vivo models, a systematic review of the literature highlighted that at least eleven travelling homeoproteins are associated with medulloblastoma: Cut like homeobox 1 (CUX1), Engrailed homeobox 1 and 2 (EN1 and EN2), Insulin gene enhancer protein ISL-1 (ISL1), LIM homeobox 1 (LHX1), Homeobox protein Nkx-2.2 (NKX2.2), OTX2, Paired box protein Pax-5,6 and 8 (PAX5, PAX6 and PAX8), as well as POU domain, class 5, transcription factor 1 (POU5F1). Overexpression of some of these homeoprotein-coding gene including OTX2 and POU5F1 was found to be associated with poor prognosis, while overexpression of PAX8 seems to have a protective effect, with a significantly better overall and progression-free survival. Research efforts to better understand the transfer mechanisms and intracellular targets of these transcription factors may offer a new range of therapeutics tools, by interfering with these roaming oncoproteins to circumscribe their associated chain reaction of genetic deregulation, or by providing protective homeoprotein supplementation with the aim of stemming tumour development by direct cancer cell penetration and reprograming.

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Fig. 1: Schematic representation of homeoproteins intercellular travel.
Fig. 2: Known non-cell autonomous roles of OTX2.
Fig. 3: Schematic representation of OTX2 levels during development and its association with medulloblastoma genesis.
Fig. 4: Interactions between homeoproteins and SHH, group 3 and group 4 medulloblastoma pathways.
Fig. 5: Different known non-cell autonomous mechanisms of other homeoproteins in vivo.
Fig. 6: Putative Pen and GAG sequences of travelling homeoproteins present in medulloblastomas.

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Acknowledgements

EV held a doctoral grant from the “Fonds pour la Recherche dans l’Industrie et l’Agriculture » (Fonds de la Recherche Scientifique, Belgium). Work in the FC laboratory (including EV and FK) was supported by grants from the « Fonds spéciaux de recherche » (FSR) of the Université catholique de Louvain, by « Projet de recherche (PDR) » fundings #T.0117.13 and #T.0039.21 and an « Equipement (EQP) » funding #U.N027.14 of the Fonds de la Recherche Scientifique (F.R.S.-FNRS, Belgium), by the « Actions de Recherche Concertées (ARC) » #17/22-079 of the « Direction générale de l’Enseignement non obligatoire et de la Recherche scientifique—Direction de la Recherche scientifique—Communauté française de Belgique » and granted by the « Académie universitaire ‘Louvain’ » and by the Association Belge contre les Maladies neuro-Musculaires (ABMM). FC is a Research Director of the F.R.S.-FNRS. Figures were created with BioRender.com.

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  1. Université catholique de Louvain, Louvain Institute of Biomolecular Science and Technology, Animal Molecular and Cellular Biology, Laboratory of Neural Differentiation, Louvain-la-Neuve, Belgium

    Eric Vigneul, Fanny Krins & Frédéric Clotman

  2. Department of Neurosurgery, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

    Eric Vigneul

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Vigneul, E., Krins, F. & Clotman, F. Of travelling homeoproteins and medulloblastomas. Oncogene 44, 3043–3051 (2025). https://doi.org/10.1038/s41388-025-03523-9

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