Biology subjects

Sprouse, F.

Publications and source records attributed to Sprouse, F..

3 recordsLinked to original sources

bioRxiv2025

Ephrin inhibition disrupts stromal-cancer crosstalk and reduces metastasis in pancreatic cancer

Cancer associated fibroblasts (CAFs) are critical drivers of disease progression and metastasis within the pancreatic tumour microenvironment. Using a 3D spheroid model of CAF-led invasion, we identified complementary expression of ephrin family receptors (EPHB2) and ligands (EPHRINB2) between cancer cells and CAFs, implicating this bidirectional signalling family in tumour progression. Through pancreatic stellate cell-derived CAFs isolated from genetically modified mouse models, where EphrinB was either lacking or modified by a gain-of-function mutation, we identified both forward and reverse signalling to be required for invasion. In a syngeneic murine orthotopic model of pancreatic cancer, we show that first-in-class tetramerisation inhibitors of Eph/Ephrin interactions can reduce local invasion in primary tumours, and significantly decrease metastatic tumour spread across multiple organ sites. Our data highlight Ephrin signalling as a critical nexus for CAF-cancer crosstalk and establish a foundation for the clinical development of targeted EPH-EPHRIN inhibitors to counter metastatic invasion.

cancer biology↗

bioRxiv2025

Eph-Ephrin Tetramerization Inhibitors Target Bidirectional Signaling to Combat Pain and Addiction

Eph receptors and Ephrin ligands are a large highly conserved family of interacting membrane-anchored molecules that form dimers, tetramers, and tetramer superclusters to become activated and signal upon cell-cell contact. While most noted for their ability to transduce bidirectional phosphotyrosine signals in development, certain Ephs and Ephrins also become overexpressed and participate in pathological situations, including EphB1 in chronic pain/addiction and EphB2 in fibroinflammatory disorders and cancer. We searched for small molecules that disrupt EphB-EphrinB receptor-ligand interactions and discovered compounds with submicromolar activity that specifically inhibit formation of the tetramer. Compounds effectively target tetramer-driven EphB1-EphrinB2 and EphB2-EphrinB2 interactions, while showing less action towards the more dimer-driven EphB4-EphrinB2 interaction. They are orally available, exhibit drug-like qualities to reduce both EphB forward and EphrinB reverse signaling, and act to blunt inflammatory pain and opioid withdrawal behaviors. Tetramer inhibitors thus present a novel way to target Eph-Ephrin macromolecular interactions and counter pathologies caused or exacerbated by excessive bidirectional signaling.

molecular biology↗

bioRxiv2025

EPHB2 promotes diet-induced MASH liver fibrosis

The EphB2 receptor tyrosine kinase is thought to participate in numerous fibroinflammatory disorders. In metabolic dysfunction-associated steatohepatitis (MASH), we find EphB2 becomes strongly overexpressed and overactive in hepatic stellate cells (HSCs) from humans with the disease and from mice fed liver-injuring high fat diets. Genetic deletion of EphB2 or inactivation of its tyrosine kinase catalytic domain suppressed diet-induced MASH fibrosis, while a kinase overactive point mutant displayed exacerbated steatosis and hepatic damage. Silencing EphB2 in primary HSCs dampened the ability of TGF-{beta}/SMAD signals to stimulate the transdifferentiation of stellate cells into profibrotic myofibroblasts, and HSC-specific deletion of the receptor, but not hepatocyte deletion, reduced liver scarring in multiple mouse models, even after fibrosis was established. Finally, a newly developed small molecule tetramerization inhibitor that targets EphB2-Ephrin receptor-ligand interactions effectively blunts inflammation and fibrosis in chemical and diet-induced liver injury models, demonstrating that therapeutically targeting EphB2 can counter MASH fibrosis.

pathology↗