p53 mutant status regulates APP maturation in colon cancer cells

The systemic influence of tumor-derived secretomes on the nervous system remains poorly understood. Here, we investigate how tumor TP53 status fundamentally alters cellular stress-handling and amyloid precursor protein (APP) processing, thereby dictating the neurotoxic potential of the tumor secretome. In colon cancer cells, we observed that p53 wild-type and p53 mutant states display strictly distinct patterns of intracellular trafficking. p53 mutant cells efficiently process APP into its mature form alongside upregulated expression of the antioxidant regulator GPX4. Conversely, p53 wild-type cells exhibit increased endoplasmic reticulum (ER) retention of immature APP, accompanied by decreased GPX4 and elevated stress-responsive ATF4 expression. Notably, in vitro cell viability and morphological analyses reveal that these distinct intracellular states translate into divergent neurotoxic profiles. Conditioned media derived from the stressed p53 wild-type cells significantly reduced cell viability and induced morphological alterations in HT22 neurons and BV2 microglia. In contrast, secretomes from p53 mutant cells exhibited comparatively reduced neurotoxicity. Collectively, our findings provide preliminary proof-of-concept that tumor TP53 mutation is linked to coordinated changes in ferroptosis-related stress regulation and APP maturation, offering novel insights into how tumor genetic status modulates tumor–neural cross-talk.