Protein S, a natural anticoagulant controls Pancreatic Ductal Adenocarcinoma by mediating both antitumor and antithrombotic effects

Abstract public domain (NIH RePORTER)

Project Summary Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal malignancies, with a 5-year survival rate below 13%. Beyond its aggressive biology, PDAC carries the highest incidence of venous thromboembolism (VTE) of any cancer, which further shortens survival and complicates therapy. This dual burden—rapid tumor progression and thrombosis—represents an urgent, unmet clinical challenge that current therapies fail to address in combination. Protein S (PS), a natural anticoagulant encoded by PROS1, uniquely integrates anticoagulant and immunemodulatory functions by binding both activated Factor IX (FIXa) and TAM family receptors (Tyro3, Axl, Mer). Our preliminary studies reveal that PS supplementation suppresses PDAC tumor growth, alleviates hypoxia, and reduces thrombosis in preclinical models—an unprecedented dual action not observed with standard anticoagulants. We hypothesize that PS deficiency drives PDAC progression and hypercoagulability, and that physiologic restoration of PS can simultaneously inhibit tumor growth and thrombosis through integrated coagulation and immune regulatory pathways. • Aim 1: Characterize plasma PS levels and PS-regulated transcriptomic signatures across PDAC cohorts to establish PS as a clinically actionable biomarker. • Aim 2: Evaluate the therapeutic efficacy of PS alone and in combination with gemcitabine in orthotopic, humanized, and organoid PDAC models to concurrently reduce tumor progression and VTE. • Aim 3: Dissect the mechanistic contribution of TAM receptor signaling versus FIXa binding in mediating PS’s antitumor effects using pharmacologic, genetic, and mutant PS approaches. Successful completion of this project will (1) define PS as a prognostic biomarker and therapeutic target, (2) establish a first-in-class, dual-action strategy that integrates thrombosis prevention with tumor control, and (3) provide mechanistic clarity to guide future ligand-specific TAM-targeted therapies. By advancing an endogenous anticoagulant with immune-regulatory capacity, this proposal offers a transformative, clinically actionable framework to address the two principal drivers of PDAC mortality—tumor progression and thrombosis. To rigorously evaluate the dual role of Protein S in regulating both thrombosis and tumor progression, we will use both orthotopic and humanized mouse models of PDAC. These in vivo models are essential because they recapitulate the complex tumor microenvironment, systemic coagulation dynamics, and tumor-stroma interactions that cannot be adequately modeled in cell culture or in vitro systems alone.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer frequently complicated by blood clots that worsen patient survival. This project investigates Protein S, a natural anticoagulant with unique immune and antitumor properties, as a dual-action therapy that targets both tumor growth and thrombosis. The findings will advance a safe, physiologic therapeutic approach with direct potential to improve outcomes for patients with PDAC.