ArticleJournal of advanced research2026
Modulation of the tumor microenvironment through BMAL1-LHX8 axis augments the sensitivity of ameloblastoma to vemurafenib.
Article in Journal of advanced research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Metformin as a potential adjunct in the treatment of mild-to-moderate ulcerative colitis: a double-blind, randomized, placebo-controlled pilot study.Internal and emergency medicine · 2025Article
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8 authors.
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Abstract
introductionAmeloblastoma (AM) frequently develops resistance to the BRAF inhibitor vemurafenib, primarily mediated by ameloblastoma-associated fibroblasts (AMFs). However, the potential contribution of the circadian clock in this resistance has not been explored.
objectivesThis study aimed to elucidate the role of the BMAL1-LHX8 axis during tumor-stroma crosstalk, and to investigate the therapeutic potential of targeting this axis to augment vemurafenib sensitivity for AM.
methodsPatient-derived AM cells and AMFs were utilized to reconstruct the stroma-rich AM tumoroid in-vitro for recapitulating the tumor-stroma interplay and assessing the pharmacological effect of vemurafenib. Time-series RNA-sequencing, luciferase assays, and CRISPR/Cas9 gene editing were used to define the transcriptional landscape and the BMAL1-LHX8 regulatory network. The efficacy of combining the clock modulator GSK4112 with vemurafenib was assessed in stroma-rich AM tumoroids and cell line-based xenograft models.
resultsPatient-derived AMFs exhibit enhanced secretory activity, and elevated metabolic and contractile functions contribute to increased stromal stiffness through ECM remodeling in AM. Tumor-stroma crosstalk was recapitulated in stroma-rich AM tumoroid, which is evidenced by the dynamic alteration of normal fibroblasts (NFs) to AMF-like state. Transcriptomic profiling of stroma-rich tumoroids revealed severe disruption of the molecular clock and LHX8 in AMFs. Functional studies demonstrated that BMAL1-driven LHX8 expression promotes pro-tumorigenic AMF activities, including growth factor secretion and ECM remodeling. Critically, pharmacological inhibition of the BMAL1-LHX8 axis with GSK4112 potently sensitized AM to vemurafenib in both stroma-rich tumoroid and xenograft models.
conclusionOur findings reveal the role of the BMAL1-LHX8 axis in underlying AMF-mediated drug resistance in AM, and propose that the molecular clock modulation in tumor-stroma crosstalk represents a potential therapeutic avenue for ameloblastoma.
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