Phase separation and RNA processingas drivers of cancer and neurodegenerative disease

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Next-generation sequencing has identified at least 50% of mutations that lack actionable therapy. Many of these mutant proteins, or proteins they interact with, are being identified as key drivers of cancer and function in transcriptional regulation and/or RNA processing. Interestingly, well-regulated RNA processing has also emerged as a critical feature of neural development and pathology. This suggests interesting parallels between the reliance of both tumor and nervous system cells on the splicing machinery. In the brain, carefully controlled alternative splicing leads to nervous system development and potentially neurodegeneration. In tumors, disregulated alternative splicing leads to disease. The commonalities between splicing, development, and cancer may reside in phase-separated nuclear bodies that have been proposed to modulate multiple steps in RNA processing. Nuclear bodies (NBs; nuclear speckles, Cajal Bodies, etc..) can be associated with specific cellular functions, like splicing, but unlike organelles that are enclosed within lipid membranes, the function of NBs depends on assemblies of proteins and nucleic acids that are not membrane-bound. This conference idea arose based upon the critical importance of RNA processing in cancer and neurobiology along with data from patient tumors showing both a mutational presence and therapeutic void. Most cancer biologists are unaware of the biophysics of protein interactions and insights into these interactions that are likely to drive the creation of novel targeted therapy. The fact that RNA processing is integral to the tumor and neuronal biology and is occurring in these poorly understood phase-separated assemblages in cells is reason to create this multidisciplinary meeting. This meeting has 5 overall objectives: (1) Gather disease specialists with experts in RNA processing and phase separation, (2) Develop multi-disciplinary research as a vehicle to advance understanding of human biology, (3) Provide opportunities to seed multi-disciplinary collaborations (4) Support trainee education about and participation in multi-disciplinary science, and (5) Catalyze new scientific discoveries that lead to therapies against otherwise non-actionable targets of human disease. The conference organizers include: Dr. Jeffrey Toretsky who has had experience at multiple levels of national and international conferences including the pediatric track chair at the American Society of Clinical Oncology. Dr. Aaron Hoskins has previous experience helping to organize programs for a NSF-funded summer school as well as many local conferences. There are virtually no conferences that have attempted to bring together such an apparent diversity of medical/scientific expertise. Without a meeting of this nature, the targeted groups of researchers would have a very low likelihood of developing collaborations. This conference will act as an enzyme to catalyze those interactions in order to advance science and medical therapies.