{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:10:21Z","timestamp":1792005021226,"version":"4.4.0"},"reference-count":83,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012128","name":"Austin Medical Research Foundation","doi-asserted-by":"publisher","award":["2025-HH"],"award-info":[{"award-number":["2025-HH"]}],"id":[{"id":"10.13039\/100012128","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012128","name":"Austin Medical Research Foundation","doi-asserted-by":"publisher","award":["2024-MN"],"award-info":[{"award-number":["2024-MN"]}],"id":[{"id":"10.13039\/100012128","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010845","name":"Pancare Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010845","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The tumour microenvironment in pancreatic ductal adenocarcinoma (PDA) regulates vascular function and therapeutic response. P21-activated kinases (PAKs) regulate cytoskeletal dynamics and angiogenesis; however, their roles in vascular reprogramming and chemotherapy responses remain unclear. This study examined the effects of a PAK1 knockdown (PAK1KD) and a PAK4 knockout (PAK4KO) on vascular remodelling in PDA. Human PANC-1 wild-type (WT), PAK1KD, and PAK4KO cells were injected subcutaneously into the flanks of SCID mice followed gemcitabine treatment. The tumour growth, vascular density, pericyte coverage, adhesion molecules, and hypoxia were determined. A proteomics study was used to identify the molecular changes involved in the vascular pathways. PAK1KD suppressed tumour growth and angiogenesis, promoted vascular normalisation, reduced hypoxia, and increased stromal ICAM-1. PAK4KO inhibited tumour growth, enlarged vessels, enhanced angiogenesis, and reduced hypoxia. PAK4KO did not affect adhesion molecules in the absence of gemcitabine, but markedly upregulated ICAM-1 and VCAM-1 with gemcitabine. Additionally, PAK4KO promoted vascular mimicry (VM) with a compromised integrity in tumour-derived vessels, but enhanced the integrity in endothelial-derived vessels. The proteomics study confirmed the enrichment of molecules in fibronectin and the VEGF pathway in PAK4KO cancer cells, along with the upregulation of EphA2, RhoA, ROCK1, ROCK2, and components of the EPH-ephrin signalling pathway, linking to enhanced VM. Neither PAK1KD nor PAK4KO increased the gemcitabine efficacy. In conclusion, PAK1KD and PAK4KO suppressed tumour growth with distinct vascular effects, but failed to enhance the gemcitabine responses, suggesting that PAK targeting reprograms the PDA vasculature, but offers limited benefit in chemotherapy-resistant models.<\/jats:p>","DOI":"10.3390\/cells14221806","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T15:38:09Z","timestamp":1763393889000},"page":"1806","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting PAK1 or PAK4 Uncovers Different Mechanisms of Vascular Reprogramming in Pancreatic Cancer"],"prefix":"10.3390","volume":"14","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, Melbourne, 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, Melbourne, VIC 3084, 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":"Olivia Newton-John Cancer Research Institute, Melbourne, VIC 3086, Australia"},{"name":"School of Cancer Medicine, La Trobe University, Melbourne, VIC 3000, 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, Melbourne, VIC 3084, Australia"},{"name":"Department of Hepatopancreatic-Biliary Surgery, Austin Health, 145 Studley Rd, Melbourne, 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, Melbourne, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.acthis.2016.01.009","article-title":"Cellular and molecular aspects of pancreatic cancer","volume":"118","author":"Gharibi","year":"2016","journal-title":"Acta Histochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3637","DOI":"10.3748\/wjg.v28.i28.3637","article-title":"Effective combinations of anti-cancer and targeted drugs for pancreatic cancer treatment","volume":"28","author":"Nishimoto","year":"2022","journal-title":"World J. 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