Biomolecular Condensation: A New Phase in Cancer Research

Abstract

Multicellularity was a watershed development in evolution. However, it also meant that individual cells could escape regulatory mechanisms that restrict proliferation at a severe cost to the organism: cancer. From the standpoint of cellular organization, evolutionary complexity scales to organize different molecules within the intracellular milieu. The recent realization that many biomolecules can "phase-separate" into membraneless organelles, reorganizing cellular biochemistry in space and time, has led to an explosion of research activity in this area. In this review, we explore mechanistic connections between phase separation and cancer-associated processes and emerging examples of how these become deranged in malignancy.

Significance: One of the fundamental functions of phase separation is to rapidly and dynamically respond to environmental perturbations. Importantly, these changes often lead to alterations in cancer-relevant pathways and processes. This review covers recent advances in the field, including emerging principles and mechanisms of phase separation in cancer.

Figure 1.

An emerging field in LLPS in cancer. A, Biomolecular polymers, such as proteins with intrinsically disordered regions, can undergo phase transitions resulting in liquid droplets with higher local density of the protein and physical properties distinct from the surroundings. Over time, the liquid droplets can mature into other phase-separated species such as gels, oligomers, or fibers. B, Increasing appreciation in studies over the last two decades exploring the connections between LLPS and cancer. Cyan bars represent the number of publications found in PubMed related to LLPS, which has steadily but continuously increased since 2000. Blue bars show a tremendous increase in the number of publications related to cancer and LLPS over the past 4 years. The pie chart reveals that only about 10% of LLPS genes annotated as cancer genes by the Cancer Gene Census have been studied to understand the molecular mechanisms behind cancer mutations.

Figure 2.

LLPS is enriched in cancer. A, Of the 287 genes with annotated cancer hallmarks in COSMIC, 53 undergo LLPS (vertical line), significantly more than observed when selecting 287 random genes with GO annotated biological processes (histogram). B, Comparison of enrichment for cancer-associated genes from A with those linked to other human diseases as well as genes that are associated with multiple diseases.

Figure 3.

Cancer hallmarks represented by phase separation genes. A, Enrichment of specific cancer hallmarks from LLPS genes. B, Bipartite network representing LLPS genes and corresponding pathways from A.

Figure 4.

Alteration of phase separation behavior by fusion proteins. Fusion proteins (bottom) formed by aberrant joining of head protein (top) and tail protein (middle) at their breakpoints (dash lines). The corresponding phase separation phenotype (loss or gain of condensates) for each of these proteins is shown on the right. Each column of cell images represents one group for comparative purpose (cells harboring fusion proteins or their corresponding head or tail parent proteins). Specific examples for the gain or loss of condensates from the literature are also shown.

Figure 5.

Therapies targeting condensates. The prevalence of cancer genes that form condensates presents an opportunity to develop new classes of therapeutics that modulate the phase separation of their targets. New drugs might be made to disrupt or prevent specific molecules from forming liquid droplets (bottom arrow), while others might stabilize the liquid droplet, blocking its dissolution or maturation into solid-phase MLOs.