Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity
Hanfeng Wang1, Yang Fan1, Weihao Chen1,2
1Senior Department of Urology, The Third Medical Center of PLA General Hospital, Beijing, China.
Abstract:
Recent studies have revealed that chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) promotes tumor progression and modulates tumor immunity by regulating programmed death-ligand 1 stability; however, its intrinsic functions and regulatory mechanisms in clear cell renal cell carcinoma (ccRCC) remain poorly understood. Here, we show that CMTM6 is upregulated in ccRCC tissues and is strongly associated with advanced tumor grades, early metastases, and a worse prognosis. CMTM6 depletion significantly impaired the proliferation, migration, and invasion of ccRCC cells in vitro and in xenograft mouse models in vivo. In addition, targeting CMTM6 promotes anti-tumor immunity, represented by increased infiltration of CD4+ and CD8+ T cells in syngeneic graft mouse models. Further research revealed that loss of CMTM6 triggered aberrant activation of DNA damage response, resulting in micronucleus formation and G2/M checkpoint arrest, finally leading to cellular senescence with robust upregulation of numerous chemokines and cytokines. Our findings show for the first time the novel role of CMTM6 in maintaining cancer genome stability and facilitating tumor-mediated immunosuppression, linking DNA damage signaling to the secretion of inflammatory factors. Targeting CMTM6 may improve the treatment of patients with advanced ccRCC.
Insights
Chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) drives clear cell renal cell carcinoma (ccRCC) progression and immune evasion. Targeting CMTM6 may offer a new therapeutic strategy for advanced ccRCC.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) is implicated in tumor progression and immune modulation.
- The specific roles and regulatory mechanisms of CMTM6 in clear cell renal cell carcinoma (ccRCC) are not well understood.
Purpose of the Study:
- To investigate the functional significance and regulatory mechanisms of CMTM6 in ccRCC.
- To explore the potential of CMTM6 as a therapeutic target in ccRCC.
Main Methods:
- Analysis of CMTM6 expression in ccRCC tissues.
- In vitro and in vivo experiments involving CMTM6 depletion in ccRCC cells and mouse models.
- Assessment of anti-tumor immunity, DNA damage response, and cellular senescence markers.
Main Results:
- CMTM6 is upregulated in ccRCC and correlates with advanced tumor grade, metastasis, and poor prognosis.
- CMTM6 depletion inhibits ccRCC cell proliferation, migration, and invasion, and enhances anti-tumor immunity (CD4+ and CD8+ T cell infiltration).
- Loss of CMTM6 activates DNA damage response, leading to genomic instability, cell cycle arrest, senescence, and inflammatory factor secretion.
Conclusions:
- CMTM6 plays a critical role in maintaining ccRCC genome stability and promoting tumor-induced immunosuppression.
- CMTM6 links DNA damage signaling to inflammatory factor secretion, highlighting its novel function in ccRCC.
- Targeting CMTM6 presents a promising therapeutic avenue for advanced ccRCC patients.
Related Concept Videos
02:23Abnormal Proliferation
02:37DNA Damage can Stall the Cell Cycle
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
02:15Replicative Cell Senescence
02:34Inhibition of Cdk Activity
02:37DNA Damage Can Stall the Cell Cycle