TSPAN13 spatially organizes epidermal growth factor signaling to support divergent functional outcomes in senescence and cancer

Here we report that the membrane scaffold factor TSPAN13 regulates endosomal condensation of the epidermal growth factor receptor (EGFR), which functions as a constitutively active signaling hub in both cellular senescence and cancer. In senescent cells and cancer cells carrying oncogenic EGFR mutations, TSPAN13 promotes liquid-liquid phase separation of the adaptor protein GRB2 with EGFR, thereby preventing its lysosomal degradation and supporting prolonged activation.

However, in senescent cells, endosomal EGFR condensates support the senescence-associated secretory phenotype, while in cancer cells, these condensates enhance proliferation. Targeting these condensates alleviates high-fat diet-induced senescence and metabolic syndrome, and also suppresses tumor growth in mice. Together, these findings identify TSPAN13 as a spatial organizer that confines active EGFR to endosomes for pathological persistence, serving as a therapeutic node in contexts characterized by abnormal EGFR activity.