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Biomolecular Condensates in Cancer

Original Dates: January 28–31, 2021


Large-scale cytological changes are a classical hallmark of cancer, although the molecular etiology of these changes has historically been poorly understood. A cell can be organized through membrane-bound organelles such as the endoplasmic reticulum and Golgi, or through membrane-less biomolecular condensates such as nuclear bodies and stress granules. While membrane-bound organelles are well-studied, the biology of membrane-less biomolecular condensates is less well-understood. It has recently been found that biomolecular condensates form through phase separation – a demixing phenomenon in which the associated acromolecular components form a dense liquid-like assembly. In addition to large well- defined membrane-less organelles, there exist a growing number of examples in which smaller biomolecular condensates mediate key biological processes. Of particular recent interest, much of the transcriptional machinery appears to consist of biomolecular condensates. The meeting is timely since the eld of biomolecular condensates in various aspects of biology has grown exponentially in recent years, and the roles of biomolecular condensates in diseases such as cancer are just beginning to be uncovered.

Misregulation of biomolecular condensates is intimately linked to cancer. For example, both PML bodies and the nucleolus are classic membraneless organelles, and both show massive morphological changes in transformed cells, a result that can now be rationalized in terms of changes to the phase behaviour associated with the underlying components. A number of specific cancers are directly linked to proteins we now know can form biomolecular condensates. The FET family proteins are a collection of RNA binding proteins that contain large unstructured low-complexity domains (LCDs). These LCDs are necessary and su cient to drive phase separation, and in a number of different cancers these LCDs translocate to oncogenic DNA binding domains, driving malignancy. A working model suggests the formation of LCD-mediated assemblies at the associated genetic loci recruits transcriptional machinery, driving unfettered gene expression. While the FET proteins lead to malignancy through oncogenes, cancer-associated mutations in the tumor suppressor SPOP disrupt its normal ability to phase separate, demonstrating that both gain-of-function and loss- of-function mutations are possible.

At the level of gene regulation, super-enhancers are biomolecular condensates that occupy specific loci on the genome and drive high-level constitutive transcription. Recent work suggests that super-enhancers form through phase separation, and that their formation at oncogenes may be a common mechanism through which transcriptional upregulation occurs in transformed cells.

Taken together, there is a growing body of work suggesting biomolecular condensates play strong roles in cancer. This is of particular interest from a therapeutic stand-point as previously ‘untreatable’ malignancy should become vulnerable through a better understanding of the molecular basis of their origins. The goal of this timely Forbeck meeting is to bring together cancer-focused medical scientists, biophysicists and cell biologist in an intimate multi- disciplinary environment to generate ideas on how study of this novel eld can lead to novel treatments for cancer.