Phase separations in oncogenesis, tumor progressions and metastasis: a glance from hallmarks of cancer

Abstract

Liquid-liquid phase separation (LLPS) is a novel principle for interpreting precise spatiotemporal coordination in living cells through biomolecular condensate (BMC) formation via dynamic aggregation. LLPS changes individual molecules into membrane-free, droplet-like BMCs with specific functions, which coordinate various cellular activities. The formation and regulation of LLPS are closely associated with oncogenesis, tumor progressions and metastasis, the specific roles and mechanisms of LLPS in tumors still need to be further investigated at present. In this review, we comprehensively summarize the conditions of LLPS and identify mechanisms involved in abnormal LLPS in cancer processes, including tumor growth, metastasis, and angiogenesis from the perspective of cancer hallmarks. We have also reviewed the clinical applications of LLPS in oncologic areas. This systematic summary of dysregulated LLPS from the different dimensions of cancer hallmarks will build a bridge for determining its specific functions to further guide basic research, finding strategies to intervene in LLPS, and developing relevant therapeutic approaches.

Keywords: Biomolecular condensate; Cancer; Liquid–liquid phase separation; Membrane-less organelle; Novel therapeutics.

Fig. 1

History of LLPS research developments. Milestone discoveries are outlined

Fig. 2

Intra-cellular MLOs within a eukaryotic cell. MLOs are distributed in the nucleus, nuclear membrane, cytoplasm, and plasma membranes of cells. Nucleolus, perinucleolar compartments, paraspeckles, Cajal bodies, transcription condensates, Gems, DNA repair foci, nuclear stress bodies, PcG bodies, histone locusbody, PML bodies, DNA replication bodies, polycombs, SPOP/DAXX bodies, super enhancers, heterochromatin, and amyloid bodies (located in nucleolus) are located in the nuclear by the LLPS. Whereas some MLOs are distributed in the nuclear membrane (Babliani bodies), cytoplasm (such as sec bodies, cGAS-DNA condensates, ER associated TIS granules, autophagosome cargo condensates, stress granule, P granules, U bodies, Virus factories, Numb/pon complex, RNA transport granules, centrosome, inclusion bodies, siganling puncta, GW bodies, germ granules, transport RNP, and proteosome bodies, metabolic granules, keratin granules), and cell plasma membrane (such as immune synapse densities, Numb/pon complex, Nephrin adhesion complexes/ signaling clusters, T cell microclusters, and ZO mediated tight junction)

Fig. 3

Basic condensates promoting features. A-C Interactions between macromolecules that facilitate phase separation. D The SH2 domain of NCK binds to Nephrin, and NCK possesses three SH3 domains that can bind the proline-rich motifs (PRMs) of N-WASP, showing a typical repetitive molecular domain (RMD) that contributes to LLPS. E Oligomerization of SPOP and its interactions with substrates can induce phase separation. F Dimerization of HP1a promotes LLPS. G–I Several classic IDRs, which consist of LCDs. J–N Fundamental interacting force between IDRs. O Formation of BMCs, from dissociation to assembly. P–S Four types of sequence variations that drive phase separation

Fig. 4

Summary of deregulated phase separations in cancer. A RTK granule formations activate RTK/MAPK signaling pathways to promote tumor proliferation. B DDX21phase separation activates MCM5, facilitating EMT signaling and modulating metastasis of colon cancer. C LLPS of 53BP1 diminish downstream targets of p53 to evade growth suppressions. D The accumulation of 53BP1 in the nuclear foci is enhanced after DNA damage, activating p53 and regulating cellular senescence. E SUMO ALT-associated PML bodies on the telomeres facilitate the replicative immortality of cancer cells. F Nuclear condensates (nYACs) generated through the LLPS of YTHDC1 (binding with m6A-mRNA) are significantly increased in AML cells. G Mutations in the FERM domain of NF2 (NF2m) robustly inhibited STING-initiated antitumor immunity by forming NF2m-IRF3 condensates. H PML nuclear bodies (NBs) serve as comprehensive ROS sensors associated with antioxidative pathways. I EBNA2 becomes part of BMCs and regulates EBV gene transcriptions. J BRD4 forms condensates with SEs to regulate angiogenesis. K NUP98-HOXA9 fusion proteins attenuate aberrant chromatin organizations. L m⁶A-modified androgen receptor (AR) mRNA phase separated with YTHDF3 responds to AR pathway inhibition (ARPI) stress in prostate cancers. M LLPS of GIRGL-CAPRIN1-GLS1 mRNA suppresses GLS1 translation and adapts to an adverse glutamine-deficient environment. N icFSP1 induces FSP1 condensates to trigger ferroptosis in the dedifferentiation of cancer cells

Fig. 5

Potential approaches to developing new cancer treatments by regulating BMCs. A Targeting driving forces to disrupt condensate formation. B Changing the modifications of components or physicochemical interaction. C Drug concentrations influenced by dynamic condensates