Biology subjects

Papadimitropoulou, A.

Publications and source records attributed to Papadimitropoulou, A..

3 recordsLinked to original sources

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

A modular lentiviral system for multiplexed gene perturbation and functional analysis reveals interdependence of hormone receptors in breast cancer growth in vivo

Precise and flexible control of gene expression is essential for dissecting gene function in complex biological systems. Although recent developments in genetic engineering and CRISPR/Cas9 technology have expanded tools for gene activation, suppression and editing, their application in physiologically relevant models remains challenging, time consuming, and expensive. Here, we present a modular, doxycycline-inducible vector system that integrates gene overexpression, shRNA-mediated knockdown, and CRISPR/Cas9-mediated regulation within a single, lentivirus-compatible system. The modular design allows rapid exchange of selection markers, epitope tags, and reporters via Gateway cloning, providing broad adaptability across experimental settings. In addition to standard fluorescent and luminescent reporters, the system includes advanced sensors, such as Fucci cell cycle reporters, to enable monitoring of cellular processes. By combining fluorescence barcoding with combinatorial genetic perturbations, the platform supports multiplexed analysis of gene function and genetic interactions through phenotypic characterization by fluorescence imaging or flow cytometry. We demonstrate its utility in vivo with breast cancer intraductal xenografts, which suggest that ER+ breast cancer cells (MCF7) rely on androgen (AR), estrogen (ER) and progesterone receptors (PR) for in vivo growth. This versatile gene perturbation system provides tight temporal control, streamlined implementation, and high-content phenotyping capacity facilitating efficient in vitro and in vivo studies while reducing the use of animals in in vivo validation experiments. It thus expands the experimental repertoire for dynamic, multigene interrogation in complex systems.

molecular 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↗