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Modulation of the tumor microenvironment through BMAL1-LHX8 axis augments the sensitivity of ameloblastoma to
Shujin Li1, Eun-Jung Kim2, Hyun-Yi Kim3
1Division in Anatomy and Developmental Biology, Department of Oral Biology, Taste Research Center, Oral Science Research Center, BK21 FOUR Project, Yonsei University College of Dentistry, Seoul, South Korea; Current Address: Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055, China.
Introduction:
Ameloblastoma (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.
Objectives:
This 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.
Methods:
Patient-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.
Results:
Patient-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.
Conclusion:
Our 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.
Insights
Ameloblastoma develops resistance to vemurafenib due to ameloblastoma-associated fibroblasts. Targeting the BMAL1-LHX8 axis with GSK4112 re-sensitizes tumors to vemurafenib, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- Ameloblastoma (AM) frequently develops resistance to vemurafenib, a BRAF inhibitor.
- Ameloblastoma-associated fibroblasts (AMFs) are key mediators of this drug resistance.
- The role of the circadian clock in AM drug resistance remains unexplored.
Purpose of the Study:
- To investigate the BMAL1-LHX8 axis in tumor-stroma crosstalk within AM.
- To explore targeting this axis to enhance vemurafenib sensitivity in AM.
Main Methods:
- Utilized patient-derived AM cells and AMFs to create in-vitro stroma-rich AM tumoroids.
- Employed time-series RNA-sequencing, luciferase assays, and CRISPR/Cas9 gene editing.
- Assessed the efficacy of combining clock modulator GSK4112 with vemurafenib in tumoroids and xenograft models.
Main Results:
- AMFs exhibit enhanced secretory, metabolic, and contractile functions, increasing stromal stiffness.
- Tumor-stroma crosstalk was recapitulated, showing normal fibroblasts transforming into AMF-like cells.
- Disruption of the molecular clock and LHX8 in AMFs was observed, with BMAL1-driven LHX8 promoting pro-tumorigenic activities.
- GSK4112 treatment sensitized AM to vemurafenib in tumoroid and xenograft models.
Conclusions:
- The BMAL1-LHX8 axis is implicated in AMF-mediated drug resistance in ameloblastoma.
- Modulating the molecular clock in tumor-stroma crosstalk presents a potential therapeutic strategy for AM.
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