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OTUD4-ZMYND8-DDX3X Axis Drives Immunosuppressive Microenvironment in Spinal Metastases of Triple-Negative Breast
Bing Liang1, Annan Hu2, Hongwei Lu2
1Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Orthopaedic Surgery, Shanghai Geriatric Medical Center, Shanghai 201104, China.
Abstract:
Triple-negative breast cancer (TNBC) exhibits a high propensity for spinal metastasis, leading to severe morbidity and limited therapeutic responses. However, the molecular mechanisms driving spinal colonization remain poorly defined. Here, we identify the epigenetic reader ZMYND8 as a key mediator of TNBC spinal metastasis. ZMYND8 is significantly upregulated in spinal metastatic lesions and correlates with adverse patient outcomes. Transcriptomic profiling reveals that spinal metastases display profoundly immunosuppressive microenvironments, with elevated M2 macrophage infiltration positively associated with ZMYND8 expression. Mechanistically, ZMYND8 functions as a scaffold protein that promotes assembly of the DDX3X-CK1ε complex, thereby activating WNT/β-catenin signaling and promoting spinal metastasis. Furthermore, we identify OTUD4 as a bona fide deubiquitinase that directly interacts with and stabilizes ZMYND8, thereby enhancing TNBC cell migration, invasion, and spinal colonization. The resulting OTUD4-ZMYND8-DDX3X signaling axis drives canonical WNT/β-catenin signaling, upregulates CSF1 expression and promotes M2 polarization of macrophages, collectively fostering invasive behavior and establishing an immunosuppressive niche conducive to spinal metastasis. Collectively, these findings establish the OTUD4-ZMYND8-DDX3X axis as a pivotal regulator of spinal metastasis in TNBC and highlight its potential as a therapeutic target for inhibiting metastatic progression.
Insights
The epigenetic reader ZMYND8 drives triple-negative breast cancer (TNBC) spinal metastasis by promoting an immunosuppressive tumor microenvironment. Targeting the OTUD4-ZMYND8-DDX3X axis may inhibit TNBC spread.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Triple-negative breast cancer (TNBC) frequently metastasizes to the spine, causing significant morbidity.
- The molecular drivers of spinal metastasis in TNBC are not well understood.
- Identifying novel therapeutic targets is crucial for improving outcomes in TNBC patients.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying spinal metastasis in TNBC.
- To identify key regulators of TNBC spinal colonization.
- To explore potential therapeutic strategies targeting metastatic pathways.
Main Methods:
- Transcriptomic profiling of spinal metastases.
- Analysis of ZMYND8 expression in patient samples.
- Investigating protein-protein interactions and signaling pathways (e.g., WNT/β-catenin).
- Assessing the role of OTUD4 and ZMYND8 in cell migration and invasion assays.
Main Results:
- ZMYND8 is upregulated in spinal metastases and associated with poor prognosis.
- Spinal metastases exhibit an immunosuppressive microenvironment with M2 macrophage infiltration.
- ZMYND8 acts as a scaffold, promoting the DDX3X-CK1ε complex and activating WNT/β-catenin signaling.
- OTUD4 stabilizes ZMYND8, enhancing TNBC cell invasion and spinal colonization.
- The OTUD4-ZMYND8-DDX3X axis upregulates CSF1 and promotes M2 macrophage polarization.
Conclusions:
- The OTUD4-ZMYND8-DDX3X signaling axis is a critical regulator of TNBC spinal metastasis.
- This axis promotes an immunosuppressive tumor microenvironment conducive to metastasis.
- Targeting this axis presents a potential therapeutic strategy for inhibiting TNBC spinal metastasis.
