Co-Leads and Co-Investigators
Aneuploidy arising from defective chromosome segregation is pervasive among nearly all solid tumors. In TP53-mutant breast cancer, the dysregulation of core mitotic transcription factors generates error-prone chromosome segregation by the scattershot upregulation of genes tied to kinetochore functions. Many of the dysregulated genes participate in a spatially-regulated positive-feedback network that controls the spindle-assembly checkpoint and kinetochore-microtubule attachments. At the heart of this network is the chromosome passenger complex (CPC)—comprised of Aurora B kinase (AURKB), INCENP, Survivin (BIRC5), and Borealin (CDCA8)—that accumulates at the inner centromere to control mitotic events. Our team discovered that the CPC phase separates upon reaching a critical concentration during mitosis, creating a dynamic subcompartment with specialized functions. How the phase-separated CPC adapts to the unbalancing effect of mitotic transcription factor dysregulation is unknown. The hypothesis of Project 1 is that phase-separated CPC acts as a “phenotypic capacitor” during mitosis by buffering small-to-moderate imbalances (storage) and unleashing dramatic rearrangements when a systems-level threshold is reached (discharge). We will test this hypothesis using biochemical reaction-diffusion models of spatially regulated CPC phase separation, which will be tailored to primary mammary organoids derived from a mosaic GEMM of triple-negative mammary cancer and extended to clinical samples through standard diagnostic assays. The specific aims are to 1) develop and validate a spatial systems model of CPC recruitment that isolates phase separation and predicts critical network imbalances in cancer-predisposed mammary organoids; 2) test the instability-generating potential of critical network imbalances by quantitatively perturbing triple-negative mammary premalignancies in vivo; and 3) leverage routine clinical diagnostics to predict druggable chromosomal instability signatures in any primary breast cancer. Patient-specific, systems-level models of aneuploidy susceptibility will nominate kinase inhibitors in the network that are predicted to shift cells from robust to fragile states of segregation fidelity.
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