Robust-to-fragile transitions of a phase-separated mitotic organelle in triple-negative breast cancer

University Of Virginia, Charlottesville VA

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Abstract

Since the submission of U54-CA274499 (“Systems Analysis of Stress-adapted Cancer Organelles (SASCO) Center”), Research Project 1 at the University of Virginia has grown increasingly enthusiastic about co-opting these formalisms to enhance its study of “Robust-to-Fragile Transitions of a Phase-Separated Mitotic Organelle in Triple-Negative Breast Cancer”. We seek to build an experimentally constrained and physically grounded reaction-diffusion model of the regulatory network surrounding the chromosome passenger complex (CPC), which senses and repairs improper microtubule attachments during metaphase (11). The CPC is recruited bivalently to the inner centromere through a pair of orthogonal histone modifications that unfold within minutes. The modifications are each amplified by positive feedbacks involving a kinase subunit of the CPC. Together, these feedbacks are thought to promote all-or-nothing behavior depending on how spindle microtubules are attached. Project 1 co-lead Stukenberg discovered in 2019 that the non-kinase subunits of the CPC will form biomolecular condensates when increased above a critical concentration that is physiologically relevant (5). In the A0 submission, we described very rudimentary ideas for how the demixed CPC could be approximated stepwise through time-evolving compartments simulated in the open-source software VCell (12, 13). However, we had no clear route to initiating or updating demixed compartments in a principled way.