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Hedgehog (Hh) signaling pathway plays an essential role during vertebrate embryonic development and tumorigenesis. It is already known that Sonic hedgehog (Shh) pathway is important for the evolution of radio and chemo-resistance of several types of tumors. Most of the brain tumors are resistant to chemotherapeutic drugs, consequently, they have a poor prognosis. So, a better knowledge of the Shh pathway opens an opportunity for targeted therapies against brain tumors considering a multi-factorial molecular overview. Therefore, emerging studies are being conducted in order to find new inhibitors for Shh signaling pathway, which could be safely used in clinical trials. Shh can signal through a canonical and non-canonical way, and it also has important points of interaction with other pathways during brain tumorigenesis. So, a better knowledge of Shh signaling pathway opens an avenue of possibilities for the treatment of not only for brain tumors but also for other types of cancers. In this review, we will also highlight some clinical trials that use the Shh pathway as a target for treating brain cancer.

Glioblastoma is an extremely aggressive glioma, resistant to radio and chemotherapy usually performed with temozolomide. One of the main reasons for glioblastoma resistance to conventional therapies is due to the presence of cancer stem-like cells. These cells could recapitulate some signaling pathways important for embryonic development, such as Sonic hedgehog. Here, we investigated if the inhibitor of the Sonic hedgehog pathway, cyclopamine, could potentiate the temozolomide effect in cancer stem-like cells and glioblastoma cell lines in vitro. The viability of glioblastoma cells exposed to cyclopamine and temozolomide treatment was evaluated by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay while the induction of apoptosis was assessed by western blot. The stemness properties of glioma cells were verified by clonogenic and differentiation assay and the expression of stem cell markers were measured by fluorescence microscopy and western blot. The glioblastoma viability was reduced by cyclopamine treatment. Cyclopamine potentiated temozolomide treatment in glioblastoma cell lines by inducing apoptosis through activation of caspase-3 cleaved. Conversely, the combined treatment of cyclopamine and temozolomide potentiated the stemness properties of glioblastoma cells by inducing the expression of SOX-2 and OCT-4. Significance: Cyclopamine plays an effect on glioblastoma cell lines but also sensibilize them to temozolomide treatment. Thus, first-line treatment with Sonic hedgehog inhibitor followed by temozolomide could be used as a new therapeutic strategy for glioblastoma patients. Competing Interest Statement The authors have declared no competing interest.

Understanding the tumor microenvironment (TME) requires experimental platforms that faithfully recapitulate its key components. Here, we present an innervated and vascularized head and neck squamous cell carcinoma (HNSCC)-on-a-chip platform built with fully defined and tunable engineered extracellular matrices (eECMs). In a stepwise increase of complexity, we first co-cultured patient-derived HNSCC cells, cancer-associated fibroblasts, and endothelial cells within tailored eECMs, revealing matrix-dependent differences in self-organization and chemotherapeutic sensitivity. We then integrated these 3D constructs into a cancer-vasculature-interface, which enabled analysis of eECM-dependent directional collective migration and metastatization. Finally, we incorporated HNSCC-specific innervation through injectable 3D human bioengineered trigeminal ganglia, establishing a chip-based innervation-tumor-vasculature tri-interface. Together, this all-human platform captures fundamental determinants of HNSCC progression, including a fully defined ECM, vasculature, and innervation, within a single modular system that is broadly adaptable for interrogating how the tumor microenvironment shapes solid tumor behavior and therapeutic responses.Competing Interest StatementThe authors have declared no competing interest.Funder Information DeclaredSwedish Research Council, https://ror.org/03zttf063, 2025-03512, 2023-04675Knut and Alice Wallenberg Foundation, KAW 2021.0186European Research Council, 101044665 PROTECTLinköping University, https://ror.org/05ynxx418Politecnico di Milano, https://ror.org/01nffqt88