Abstract
Cerebellum tissue invasion and dissemination are major drivers of recurrence and metastatic spread in medulloblastoma (MB), yet no invasion-inhibitory therapy is currently available. The serine/threonine kinase MAP4K4 is highly expressed in MB and promotes invasive behavior downstream of growth factor signaling, while its physiological postnatal downregulation suggests that disrupted developmental control may contribute to tumor pathogenesis. Here, we investigate pharmacological targeting of MAP4K4 using famlasertib, a CNS-penetrant and neuroprotective MAP4K inhibitor, as a strategy to suppress invasion in MB. Using 3D invasion assays, quantitative live-cell microscopy, and phospho-proteomics, we demonstrate that famlasertib markedly reduces invasive behavior and single-cell motility of MB cells. Zebrafish larval and tissue models further confirm anti-invasive efficacy without detectable developmental toxicity at effective concentrations. Mechanistically, MAP4K inhibition alters kinase signaling linked to cytoskeletal remodeling, leading to suppressed F-actin dynamics, increased cell clustering, and enhanced cortical accumulation of tight junction protein 1 (TJP1). Collectively, our findings confirm MAP4Ks as a therapeutic targetable regulators of MB invasion and establish famlasertib as a candidate migrastatic agent that restrains tumor cell dissemination while preserving developmental integrity.
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Abstract
Cerebellum tissue invasion and dissemination are major drivers of recurrence and metastatic spread in medulloblastoma (MB), yet no invasion-inhibitory therapy is currently available. The serine/threonine kinase MAP4K4 is highly expressed in MB and promotes invasive behavior downstream of growth factor signaling, while its physiological postnatal downregulation suggests that disrupted developmental control may contribute to tumor pathogenesis. Here, we investigate pharmacological targeting of MAP4K4 using famlasertib, a CNS-penetrant, neuroprotective MAP4K inhibitor, as a strategy to suppress invasion in MB.
Using 3D invasion assays and quantitative live-cell microscopy, we demonstrate that famlasertib markedly reduces invasive behavior and single-cell motility of MB cells. Organotypic cerebellum tissue and orthotopically implanted zebrafish larval models further confirm anti-invasive efficacy without detectable developmental toxicity at effective concentrations. Phospho-proteomics and functional analyses revealed that MAP4K inhibition alters kinase signaling linked to cytoskeletal remodeling, leading to suppressed F-actin dynamics, increased cell clustering, and enhanced cortical accumulation of tight junction protein 1 (TJP1).
Collectively, our findings confirm MAP4Ks as therapeutically targetable regulators of MB invasion and establish famlasertib as a candidate migrastatic agent that restrains tumor cell dissemination while preserving developmental integrity.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
This project was funded by projects from the Swiss National Science Foundation (Sinergia_CRSII5_202245/1, SNF_310030_188793), the Stiftung für Wissenschaftliche Forschung an der Universität Zürich (STWF-22-005) and Childhood Cancer Research Foundation Switzerland.
Title has been changed, author list adjusted, abstract modified, new data included in Fig. 2l.
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