Emerging Roles of Liquid–Liquid Phase Separation in Cancer: From Protein Aggregation to Immune-Associated Signaling

Abstract

Liquid–liquid Phase Separation (LLPS) of proteins and nucleic acids has emerged as a new paradigm in the study of cellular activities. It drives the formation of liquid-like condensates containing biomolecules in the absence of membrane structures in living cells. In addition, typical membrane-less condensates such as nuclear speckles, stress granules and cell signaling clusters play important roles in various cellular activities, including regulation of transcription, cellular stress response and signal transduction. Previous studies highlighted the biophysical and biochemical principles underlying the formation of these liquid condensates. The studies also showed how these principles determine the molecular properties, LLPS behavior, and composition of liquid condensates. While the basic rules driving LLPS are continuously being uncovered, their function in cellular activities is still unclear, especially within a pathological context. Therefore, the present review summarizes the recent progress made on the existing roles of LLPS in cancer, including cancer-related signaling pathways, transcription regulation and maintenance of genome stability. Additionally, the review briefly introduces the basic rules of LLPS, and cellular signaling that potentially plays a role in cancer, including pathways relevant to immune responses and autophagy.

An integrative multi-omics analysis based on liquid–liquid phase separation delineates distinct subtypes of lower-grade glioma and identifies a prognostic signature

“…For example, the LLPS of cyclic GMP-AMP synthase (cGAS) promotes the secondary messenger cyclic GMP-AMP (cGAMP) production and innate immune signaling [ 42 ]. A large proportion of biomolecules in the transmembrane signaling receptors of T cells might phase separate into clusters to facilitate the transduction of signals and regulate immune responses of tumors [ 43 ]. In this study, LS1 had higher immune scores and stroma scores, but lower tumor purity compared with other subtypes, indicating that LS1 was surrounded by more nontumor components.…”

A novel model based on liquid‐liquid phase separation–Related genes correlates immune microenvironment profiles and predicts prognosis of lung squamous cell carcinoma

“… 26 , 27 Recently, some studies tried to interpret immune activities in tumor microenvironment from the perspective of LLPS. 17 , 18 However, this field is still in its infancy. In the present study, our analysis identified a series of immune‐related processes were correlated with LLPS in LUSC, including pathways involving different immune cells, adaptive and innate immune response, and immune checkpoint.…”

“… 15 , 16 Emerging evidence also revealed the correlation of LLPS‐related activities with anti‐tumoral immune response, providing a new perspective for understanding tumor immunology. 17 , 18 All these findings indicated the potential impact of LLPS on cancer development by its direct and indirect effects.…”

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

“…Alterations to the glycolytic pathways are often observed during the early stages of neurodegenerative diseases where mitochondrial dysfunction and reduced ATP levels may contribute to protein aggregation [ 515 ]. Increasingly, the pathogenic aggregation of MLOs such as stress granules, p53, FUS, TDP-43, and tau exhibiting dysregulated LLPS is believed to play a major part in the development of neurodegeneration and cancer [ 12 , 516 , 517 , 518 ].…”