{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T14:32:39Z","timestamp":1783521159215,"version":"3.55.0"},"reference-count":53,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Austin Medical Research Foundation","award":["2023-HH"],"award-info":[{"award-number":["2023-HH"]}]},{"name":"Austin Medical Research Foundation","award":["2024-MN"],"award-info":[{"award-number":["2024-MN"]}]},{"name":"Pancare Foundation","award":["2023-HH"],"award-info":[{"award-number":["2023-HH"]}]},{"name":"Pancare Foundation","award":["2024-MN"],"award-info":[{"award-number":["2024-MN"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDA) exhibits diverse molecular aberrancies that contribute to its aggressive behaviour and poor patient survival. P-21-activated kinase 1 (PAK1) and PAK4 drive the tumorigenesis of PDA. However, their roles in tumour vasculature and the impact on immune response are unclear. This study aims to investigate the effects of PAK1 and PAK4 on tumour vasculature, immune cell infiltration, and the connection between using PAK1-knockout (KO), PAK4 KO, and wild-type (WT) PDA cells in cell-based and mouse experiments. Tumour tissues isolated from a syngeneic mouse model were immuno-stained to determine the changes in tumour vasculature and immune cell infiltration\/activation, followed by a proteomic study to assess biological processes involved. PAK1KO or PAK4KO suppressed tumour growth by reducing angiogenesis while enhancing vascular normalisation, enhanced the infiltration\/activation of T-cells and dendritic cells associated with upregulation of ICAM-1 and VCAM-1 in the tumour microenvironment, and stimulated vascular immune crosstalk via an ICAM-1-mediated mechanism. This was supported by proteomic profiles indicating the regulation of endothelial cell and leukocyte trans-endothelial migration in PAK1- or PAK4-knockout tumours. In conclusion, PAK1KO or PAK4KO enhanced tumour vascular normalisation while reducing angiogenesis, stimulating immune cell infiltration and activation to suppress tumour growth.<\/jats:p>","DOI":"10.3390\/ijms26178357","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T11:41:12Z","timestamp":1756381272000},"page":"8357","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["P-21 Kinase 1 or 4 Knockout Stimulated Anti-Tumour Immunity Against Pancreatic Cancer by Enhancing Vascular Normalisation"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0716-0085","authenticated-orcid":false,"given":"Arian","family":"Ansardamavandi","sequence":"first","affiliation":[{"name":"Department of Surgery, Austin Precinct, The University of Melbourne, 145 Studley Rd, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea","family":"Dumesny","sequence":"additional","affiliation":[{"name":"Department of Surgery, Austin Precinct, The University of Melbourne, 145 Studley Rd, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Surgery, Austin Precinct, The University of Melbourne, 145 Studley Rd, Heidelberg, VIC 3084, Australia"},{"name":"Department of General Surgery, Monash Health, Clayton, VIC 3806, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4718-2097","authenticated-orcid":false,"given":"Li","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Anatomy & Physiology, University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5772-6051","authenticated-orcid":false,"given":"Sarah","family":"Ellis","sequence":"additional","affiliation":[{"name":"School of Cancer Medicine, La Trobe University, Melbourne, VIC 3000, Australia"},{"name":"Olivia Newton-John Cancer Research Institute, Heidelberg, Melbourne, VIC 3086, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7861-6719","authenticated-orcid":false,"given":"Ching-Seng","family":"Ang","sequence":"additional","affiliation":[{"name":"Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrdad","family":"Nikfarjam","sequence":"additional","affiliation":[{"name":"Department of Surgery, Austin Precinct, The University of Melbourne, 145 Studley Rd, Heidelberg, VIC 3084, Australia"},{"name":"Department of Hepatopancreatic-Biliary Surgery, Austin Health, 145 Studley Rd, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2342-8750","authenticated-orcid":false,"given":"Hong","family":"He","sequence":"additional","affiliation":[{"name":"Department of Surgery, Austin Precinct, The University of Melbourne, 145 Studley Rd, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12029-025-01183-2","article-title":"Trends in the global incidence of pancreatic cancer and a brief review of its histologic and molecular subtypes","volume":"56","author":"Leiphrakpam","year":"2025","journal-title":"J. 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