Pancreatic cancer disrupts the adult hippocampal neurogenic niche

Pancreatic cancer (PC) exhibits a striking association with depression, with neuropsychiatric symptoms frequently preceding diagnosis. However, the biological mechanisms linking pancreatic tumor development to central nervous system dysfunction remain poorly understood. Here, we investigated the impact of PC progression on adult hippocampal neurogenesis using complementary orthotopic xenograft and genetically engineered mouse models. Tumor-bearing mice developed depressive-like behavioral abnormalities accompanied by reduced adult hippocampal neurogenesis, including depletion of neural stem cell populations and immature neurons in both dorsal and ventral dentate gyrus regions. In the genetic model, neurogenic impairment progressed in parallel with disease severity. Exposure of primary hippocampal neural stem cells to serum derived from tumor-bearing mice selectively impaired cell survival, indicating that circulating factors are sufficient to compromise neurogenic capacity. Consistent with this, cytokine profiling revealed profound systemic inflammatory alterations, with IL-6 emerging as the only cytokine consistently elevated across both models. Together, our findings identify disruption of the adult hippocampal neurogenic niche as a previously unrecognized consequence of pancreatic cancer progression and provide a biological framework for pancreatic cancer-associated depression.