Kogionou, P. | Search bioRxiv

bioRxiv2026

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.

cancer biology↗

bioRxiv2025

Pharmacological targeting of SOS1-RAS interaction triggers pancreatic β-cell proliferation and sustainably reverses diabetic hyperglycemia

Clinical studies have suggested that restoring a sufficient mass of functional {beta} cells can provide an effective treatment option for diabetes, however, it remains unclear whether this can be achieved through pharmacological stimulation of endogenous {beta}-cell proliferation. We demonstrate here that ectopic expression of a constitutively active form of Kras (KrasG12D) exclusively in pancreatic endocrine cells suppresses {beta}-cell proliferation, resulting in a dramatic reduction in {beta}-cell numbers and islet size. Conversely, we demonstrate that the potent and selective SOS1-RAS interaction inhibitor BI-3406 promotes unprecedented levels of {beta}-cell proliferation in primary human islets, both in culture and following transplantation in immunocompromised diabetic mice. Importantly, using murine models of streptozotocin-induced diabetes, we show that BI-3406 treatment restores {beta}-cell mass, leading to a gradual normalization of blood glucose and insulin levels, as well as to sustainable improvement in glucose tolerance. Our data provide the first pre-clinical evidence of an orally bioavailable KRAS inhibitor that can directly induce {beta}-cell regeneration.

cell biology↗