Targeting PAK1 or PAK4 Uncovers Different Mechanisms of Vascular Reprogramming in Pancreatic Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• The tumor microenvironment critically influences pancreatic ductal adenocarcinoma (PDA) vascular function and treatment outcomes.
• P21-activated kinases (PAKs) are implicated in cytoskeletal dynamics and angiogenesis, but their specific roles in PDA vascular reprogramming and chemotherapy response are not fully understood.

Purpose of the Study:

• To investigate the effects of PAK1 knockdown (PAK1KD) and PAK4 knockout (PAK4KO) on vascular remodeling and chemotherapy response in PDA.
• To elucidate the molecular mechanisms underlying vascular changes induced by PAK targeting in PDA.

Main Methods:

• Human PANC-1 wild-type, PAK1KD, and PAK4KO cells were xenografted into SCID mice and treated with gemcitabine.
• Tumor growth, vascular density, pericyte coverage, adhesion molecules, and hypoxia were assessed.
• Proteomics analysis was employed to identify molecular alterations in vascular pathways.

Main Results:

• PAK1KD suppressed tumor growth, angiogenesis, and hypoxia while promoting vascular normalization and increasing stromal ICAM-1.
• PAK4KO inhibited tumor growth, enhanced angiogenesis, and reduced hypoxia, but also enlarged vessels and promoted vascular mimicry (VM).
• PAK4KO upregulated adhesion molecules (ICAM-1, VCAM-1) with gemcitabine and revealed distinct effects on tumor-derived versus endothelial-derived vessel integrity. Proteomics identified enrichment in fibronectin and VEGF pathways, and upregulation of EphA2, RhoA, ROCK1/2, and EPH-ephrin signaling components, correlating with enhanced VM.

Conclusions:

• PAK1KD and PAK4KO exhibit distinct vascular effects and suppress tumor growth in PDA models.
• Neither PAK1KD nor PAK4KO enhanced gemcitabine efficacy, indicating that while PAK targeting reprograms PDA vasculature, it provides limited benefit in chemotherapy-resistant settings.