A PTX3/TLR4 axis sustains sonic hedgehog-medulloblastoma growth and defines a new therapeutic vulnerability

@article{filiberti2026ptx3tlr4,
  title = {{A PTX3/TLR4 axis sustains sonic hedgehog-medulloblastoma growth and defines a new therapeutic vulnerability}},
  author = {Serena Filiberti and Camilla Tavani and Elena Somenza and Nicolas Tassone and Davide Capoferri and Chiara Romani and Arianna Giacomini and Elisabetta Grillo and Marco Ritelli and Tiziana Annese and Antonio d’Amati and Martina Canton and Elena Mariotto and Roberta Bortolozzi and Giampietro Viola and Andrei Turtoi and Pietro Luigi Poliani and Marta Turati and Roberto Ronca},
  journal = {Neuro-Oncology},
  year = {2026},
  month = jul,
  doi = {10.1093/neuonc/noag167},
  url = {https://doi.org/10.1093/neuonc/noag167},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - A PTX3/TLR4 axis sustains sonic hedgehog-medulloblastoma growth and defines a new therapeutic vulnerability
AU  - Serena Filiberti
AU  - Camilla Tavani
AU  - Elena Somenza
AU  - Nicolas Tassone
AU  - Davide Capoferri
AU  - Chiara Romani
AU  - Arianna Giacomini
AU  - Elisabetta Grillo
AU  - Marco Ritelli
AU  - Tiziana Annese
AU  - Antonio d’Amati
AU  - Martina Canton
AU  - Elena Mariotto
AU  - Roberta Bortolozzi
AU  - Giampietro Viola
AU  - Andrei Turtoi
AU  - Pietro Luigi Poliani
AU  - Marta Turati
AU  - Roberto Ronca
PY  - 2026
DA  - 2026/07/23
JO  - Neuro-Oncology
DO  - 10.1093/neuonc/noag167
UR  - https://doi.org/10.1093/neuonc/noag167
AB  - Background: Sonic hedgehog-medulloblastoma (SHH-MB) represents a biologically diverse and clinically challenging subgroup, especially in high-risk variants characterized by metastatic dissemination. Despite progress in molecular stratification, current treatments rely on intensive multimodal regimens that are associated with substantial long-term neurotoxicity. Identifying novel oncogenic mechanisms that can be therapeutically exploited is therefore a critical priority.  Methods: We combined transcriptomic analyses of patient datasets with immunohistochemistry, RNAscope, and protein profiling to evaluate PTX3 expression in MB subgroups. Functional studies were performed in SHH-MB cell lines following PTX3 knockdown or knockout. Effects on proliferation, migration, and angiogenesis were assessed through multiple in vitro assays. In vivo relevance was tested using subcutaneous and orthotopic xenograft models. Mechanistic insights were obtained through phospho-kinase arrays, Western blotting, and GSEA. A high-throughput drug screen and combination studies with specific inhibitors and standard chemotherapy (vincristine/cisplatin/cyclophosphamide; VCC) were performed to assess therapeutic potential.  Results: Our results reveal that PTX3 was strongly enriched in SHH-MB subgroup, where it supported proliferation, motility, and angiogenesis. Mechanistically, PTX3 activated a TLR4-dependent IRAK1/PI3K-Akt/GSK-3/β-catenin signaling cascade. Genetic downregulation or pharmacologic blockade of PTX3-TLR4 significantly reduced tumor growth and angiogenesis in vivo. Moreover, the TLR4 inhibitor TAK-242 markedly impacted SHH-MB growth in vitro, and combination therapy of TAK-242 and VCC produced additive/synergistic effects in vitro and significantly prolonged survival in orthotopic SHH-MB-bearing mice.  Conclusions: Our findings identify PTX3-TLR4 signaling as key oncogenic driver and a promising therapeutic ­vulnerability in SHH-MB. Targeting this pathway enhances the efficacy of standard therapy and represents a rationale for mechanism-based combination strategies.
SN  - 1522-8517
SN  - 1523-5866
ER  -