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The Effects of PAK-Regulated Tumour Vasculature on Gemcitabine Response of Pancreatic Cancer
by
, , , ,
Arian Ansardamavandi
1
,
Chelsea Dumesny
1,
Yi Ma
1,2,
Li Dong
3,
Sarah Ellis
4,5,
Ching-Seng Ang
6
,
Mehrdad Nikfarjam
1,7 and
Hong He
1,* 1
Department of Surgery, Austin Precinct, The University of Melbourne, 145 Studley Rd, Melbourne, VIC 3084, Australia
2
Department of General Surgery, Monash Health, Clayton, VIC 3806, Australia
3
Department of Anatomy & Physiology, The University of Melbourne, Melbourne, VIC 3010, Australia
4
School of Cancer Medicine, La Trobe University, Melbourne, VIC 3000, Australia
5
Olivia Newton-John Cancer Research Institute, Heidelberg, Melbourne, VIC 3086, Australia
6
Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia
7
Department of Hepatopancreatic-Biliary Surgery, Austin Health, 145 Studley Rd, Melbourne, VIC 3084, Australia
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(21), 3434; https://doi.org/10.3390/cancers17213434 (registering DOI)
Submission received: 9 September 2025
/
Revised: 7 October 2025
/
Accepted: 23 October 2025
/
Published: 26 October 2025
(This article belongs to the Section Molecular Cancer Biology)
Simple Summary
Pancreatic cancer is one of the deadliest cancers, partly because its abnormal blood vessels hinder treatments from reaching the tumour effectively. P21-activated kinase 1 (PAK1) and PAK4 play key roles in tumorigenesis, but their specific effects on tumour blood vessels and treatment response are not well understood. In this study, we used immunocompromised mice models to investigate how knockout PAK1 and/or PAK4 change the structure and function of tumour blood vessels and how these changes affect chemotherapy outcomes. We found that PAK1 knockout reduced tumour growth and new blood vessel formation while improving vessel normalisation, whereas PAK4 knockout increased vessel diameter and sensitised cancer cells to chemotherapy. The double knockout of PAK1 and PAK4 did not inhibit tumour growth significantly, but stimulated vascular normalisation, indicating an outcome balanced between PAK1 and PAK4. These findings indicate that PAK1 and PAK4 differentially regulated tumour vasculature and cancer response to chemotherapy.
Abstract
Background/Objectives: The tumour microenvironment in pancreatic ductal adenocarcinoma (PDA) is highly complex, influencing both vascular function and therapy response. P21-activated kinases (PAKs) are key regulators of the cellular and immune system, but the specific roles of PAK1 and PAK4 in pancreatic tumour vasculature and chemotherapy sensitivity are unclear. This study investigated the effects of PAK1 and PAK4 on tumour vasculature and therapeutic response in an immunocompromised mouse model. Methods: KPC-derived wild type (WT), PAK1 knockout (KO), PAK4KO, or PAK1&4KO pancreatic cancer cells were injected subcutaneously into SCID mice, followed by gemcitabine treatment. Tumour growth, vessel density, pericyte coverage, and endothelial adhesion molecule expression were analysed by histology and immunostaining. A proteomic study was used to identify protein changes. Results: PAK1KO significantly reduced tumour growth, enhanced vascular normalisation, upregulated stromal ICAM-1 and VCAM-1, but reduced gemcitabine efficacy. PAK4KO did not inhibit tumour growth but increased vessel diameter and enhanced gemcitabine efficacy. Proteomics study indicated that PAK1KO downregulated proteins involved in the VEGF pathway, while PAK4KO upregulated most proteins involved in the VEGF pathway and downregulated DNA repair proteins, contributing to improved chemotherapy sensitivity. The double knockout of PAK1 and PAK4 did not inhibit tumour growth, although it stimulated vascular normalisation, indicating an outcome balanced between PAK1 and PAK4. Conclusions: PAK1 and PAK4 differentially regulated pancreatic tumour vasculature and chemotherapy response. PAK1KO suppressed tumour growth by reducing angiogenesis and enhancing vascular normalisation, whereas PAK4KO enhanced gemcitabine efficacy through vessel dilation.
