Biomolecular Condensates and Cancer

Abstract

Malignant transformation is characterized by dysregulation of diverse cellular processes that have been the subject of detailed genetic, biochemical, and structural studies, but only recently has evidence emerged that many of these processes occur in the context of biomolecular condensates. Condensates are membrane-less bodies, often formed by liquid-liquid phase separation, that compartmentalize protein and RNA molecules with related functions. New insights from condensate studies portend a profound transformation in our understanding of cellular dysregulation in cancer. Here we summarize key features of biomolecular condensates, note where they have been implicated-or will likely be implicated-in oncogenesis, describe evidence that the pharmacodynamics of cancer therapeutics can be greatly influenced by condensates, and discuss some of the questions that must be addressed to further advance our understanding and treatment of cancer.

Keywords: biomolecular condensates; cancer; cancer therapeutics; dysregulated state; intrinsically disordered protein; phase separation.

Figure 1.. Biomolecular condensates located throughout the nucleus and cytoplasm

Cartoon depicting the cell composed of various condensates that compartmentalize biomolecules involved in shared processes. PML, promyelocytic leukemia protein; SPOP, Speckle-type POZ protein.

Figure 2.. Condensate-promoting features of biomolecules

(A) Condensate-promoting features of biomolecules include intrinsically disordered regions and repeated modular domains as well as DNA and RNA. (B) Electrostatic surface potential plots of interactions governing partitioning of biomolecules into condensates, including hydrophobic, pi-pi, electrostatic, and pi-cation interactions.

Figure 3.. Compartmentalization, localization, and regulation are common features of condensates

(A) Compartmentalization allows for high local concentrations of biomolecules and their substrates, as well as exclusion of other molecules. (B) Localization of nuclear condensates can be mediated by proteins that bind to specific DNA or RNA sequences (left), and cytoplasmic condensates can form at sites on the plasma membrane (right). (C) Regulation of condensates can occur at many levels, for example, post-translational modifications (PTMs) of molecules or the presence of RNA may change the properties that influence formation. The chemical environment of condensates dictates selective partitioning, e.g., BRD4 is preferentially concentrated in euchromatin condensates versus heterochromatin condensates.

Figure 4.. Condensate compartments dysregulated in malignant cells

(A) Cartoon depicting a transcriptional condensate with various components that have been reported to be altered in cancer. (B) Recurrent mutations affecting histones, chromatin modifiers, and proteins that interact with modified biomolecules can alter chromatin condensates. (C) Translocation of the IgH super-enhancer (SE) to the MYC locus is an oncogenic event in aggressive B cell lymphomas that is likely to result in the formation of a membrane less compartment at the MYC gene. (D) Elevated levels of the oncogenic MYC protein in metastatic tumor cells may alter the behavior of transcriptional condensates in these cells.

Figure 5.. Hallmarks of cancer incorporate processes that involve diverse biomolecular condensates

Biomolecular condensates are involved in most processes that have been called hallmarks of cancer (modified from Hanahan and Weinberg, 2011).

Figure 6.. Condensates and drug action in cancer

(A) Partitioning of drugs into specific non-membrane-bound condensate compartments within cells can increase the concentration and efficacy of the drug. (B) Drug resistance in cancer cells might occur through overexpression of a condensate-promoting protein. This mediates formation of larger condensates with resulting dilution of the drug, rendering the drug less effective. (C) Certain condensates appear to be sensitive to disruption by small-molecule drugs. (D) Drugs targeting enzymes mediating post-translational modifications are likely to affect condensate formation.