A phosphoinositide diffusion barrier prevents aneuploidy and tumorigenesis

Breast cancer (BC) is often driven by genetic abnormalities such as aneuploidy, which are strongly linked to increased tumor aggressiveness and poor clinical outcomes. Understanding the mechanisms behind aneuploidy is crucial for identifying new therapeutic vulnerabilities in cancer. Failures in cytokinesis and subsequent tetraploidization are early events that contribute to aneuploidy and drive tumor progression. Phosphoinositides (PtdIns) play a key role in this process by directing membrane remodeling during cytokinesis. However, the free diffusion of PtdIns across membranes presents a challenge for their selective localization and compartmentalization. Here we identified a Septin-based barrier at the midbody, which restricts PtdIns diffusion and enables the selective accumulation of PI(4)P in early cytokinesis. The targeted enrichment of PI(4)P is essential for preventing furrow regression and tetraploidization by enabling a selective interaction with MKLP1-RACGAP1 at the midbody, which connects the plasma membrane to the intercellular bridge. Disruption of this interaction—through reduced PI(4)P levels via PI4KA knockdown or inhibition—leads to tetraploidization, aneuploidy, and tumor progression.