Induced phase separation of mutant NF2 imprisons the cGAS-STING machinery to abrogate antitumor immunity

Meng, Fansen; Yu, Zhengyang; Zhang, Dan; Chen, Shasha; Guan, Hongxin; Zhou, Ruyuan; Wu, Qirou; Zhang, Qian; Liu, Shengduo; Ramani, Mukesh Kumar Venkat; Yang, Bing; Ba, Xiao-Qun; Zhang, Jing; Huang, Jun; Bai, Xueli; Qin, Jun; Feng, Xin‐Hua; Ouyang, Songying; Zhang, Yan Jessie; Liang, Tingbo; Xu, Pinglong

doi:10.1016/j.molcel.2021.07.040

Cited by 80 publications

(61 citation statements)

References 89 publications

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“…For example, Meng et al observed phase-separated droplets formed by Merlin (NF2) in dissected samples from vestibular schwannoma patients. 25 In addition, emerging evidence suggests that biomolecular condensates affect the pharmacodynamic properties of antineoplastic medicines; therefore, regulating the LLPS process could be a potential strategy for novel cancer therapies. Therefore, we evaluate the great potential of effectively regulating LLPS in anticancer therapy and propose perspectives on condensates that might contribute to future investigations in oncology.…”

Section: Introductionmentioning

confidence: 99%

Liquid–liquid phase separation in tumor biology

Tong

Tang

et al. 2022

Sig Transduct Target Ther

110

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Liquid–liquid phase separation (LLPS) is a novel principle for explaining the precise spatial and temporal regulation in living cells. LLPS compartmentalizes proteins and nucleic acids into micron-scale, liquid-like, membraneless bodies with specific functions, which were recently termed biomolecular condensates. Biomolecular condensates are executors underlying the intracellular spatiotemporal coordination of various biological activities, including chromatin organization, genomic stability, DNA damage response and repair, transcription, and signal transduction. Dysregulation of these cellular processes is a key event in the initiation and/or evolution of cancer, and emerging evidence has linked the formation and regulation of LLPS to malignant transformations in tumor biology. In this review, we comprehensively summarize the detailed mechanisms of biomolecular condensate formation and biophysical function and review the recent major advances toward elucidating the multiple mechanisms involved in cancer cell pathology driven by aberrant LLPS. In addition, we discuss the therapeutic perspectives of LLPS in cancer research and the most recently developed drug candidates targeting LLPS modulation that can be used to combat tumorigenesis.

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Section: Introductionmentioning

confidence: 99%

Liquid–liquid phase separation in tumor biology

Tong

Tang

et al. 2022

Sig Transduct Target Ther

110

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“…Besides, Neurofibromin 2 (NF2/Merlin/schwannomin) is a classical tumor suppressor and naturally occurring mutations in the FERM domain could transform it into a profound suppressor, which can inhibit the cGAS-STING pathway by blocking STING-mediated DNA sensing. This evidence may provide some clues to the pathogenesis of NF2-related tumors ( 35 ).…”

Section: Overview Of the Cgas/sting Pathwaymentioning

confidence: 86%

The cGAS/STING Pathway: A Novel Target for Cancer Therapy

Gan

Han

et al. 2022

Front. Immunol.

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As a DNA receptor, cyclic GMP-AMP synthase (cGAS) plays a crucial role in the immune system by recognizing abnormal DNA in the cytoplasm and activating the stimulator of interferon genes (STING) signaling pathway. This signaling cascade reaction leads to an immune response produced by type I interferon and other immune mediators. Recent advances in research have enhanced our current understanding of the potential role of the cGAS/STING pathway in anticancer therapy; however, in some cases, chronic STING activation may promote tumorigenesis. The present review article discusses the biological mechanisms of the cGAS/STING pathway, its dichotomous role in tumors, and the latest advances with respect to STING agonists and antagonists.

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“…Another cancer-associated mutation that alters signaling pathways occurs in the tumor suppressor NF2 (Neurofibromin 2). The mechanism by which NF2 mutations drive cancer is unknown but recent results show that mutation in the FERM domain of NF2 lead to a gain-of-function ability to form biomolecular condensates that sequester and inactivate IRF3 and TBK1, disrupting the cGAS-Sting pathway ( Figure 1 B) [ 41 ]. The NF2 condensates exhibited a quick recovery after photobleaching, suggesting that the sequestration model for the cGAS-Sting pathway is not absolute.…”

Section: Introductionmentioning

confidence: 99%

Liquid–Liquid Phase Separation in Cancer Signaling, Metabolism and Anticancer Therapy

Igelmann

Lessard²,

Ferbeyre

2022

Cancers

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The cancer state is thought to be maintained by genetic and epigenetic changes that drive a cancer-promoting gene expression program. However, recent results show that cellular states can be also stably maintained by the reorganization of cell structure leading to the formation of biological condensates via the process of liquid–liquid phase separation. Here, we review the data showing cancer-specific biological condensates initiated by mutant oncoproteins, RNA-binding proteins, or lincRNAs that regulate oncogenic gene expression programs and cancer metabolism. Effective anticancer drugs may specifically partition into oncogenic biological condensates (OBC).

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Induced phase separation of mutant NF2 imprisons the cGAS-STING machinery to abrogate antitumor immunity

Cited by 80 publications

References 89 publications

Liquid–liquid phase separation in tumor biology

Liquid–liquid phase separation in tumor biology

The cGAS/STING Pathway: A Novel Target for Cancer Therapy

Liquid–Liquid Phase Separation in Cancer Signaling, Metabolism and Anticancer Therapy

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