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Operating as a MAP kinase kinase kinase (MAP3K) within the STE20 family, TAOK3 coordinates diverse cellular processes. In the PDA parenchyma, TAOK3 maintains the cancer stem cell (CSC) phenotype by enforcing a strict DNA damage response checkpoint. Within the TME, TAOK3 facilitates local invasion by regulating endosomal trafficking for invadopodia assembly. Furthermore, TAOK3 exerts immunomodulatory effects, dictating macrophage polarization and preserving canonical T-cell receptor (TCR) signaling by inducing the degradation of the SHP-1 phosphatase. Systemically, tumor-derived signals establish a pathogenic feedforward loop with skeletal muscle whereby TAOK1 activity is upregulated in peripheral skeletal muscle to drive muscle atrophy secondary to TAOK3 expression in the primary tumor. The recent development of specific structural inhibitors with dual-acting natural bioactivities, provides a compelling preclinical foundation to transition TAOK3 from prognostic biomarker to premier therapeutic target in pancreatic oncology.<\/jats:p>","DOI":"10.3390\/ijms27146290","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T06:49:36Z","timestamp":1784184576000},"page":"6290","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thousand-And-One Kinase 3 in Pancreatic Ductal Adenocarcinoma Stemness, Microenvironment and Therapy Resistance"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8461-3933","authenticated-orcid":false,"given":"James","family":"Tai","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3052, Australia"},{"name":"Department of Surgery, Austin Health, 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":"Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3052, Australia"},{"name":"Department of Surgery, Austin Health, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0165-1564","authenticated-orcid":false,"given":"Marcos V.","family":"Perini","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3052, Australia"},{"name":"Department of Surgery, Austin Health, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrdad","family":"Nikfarjam","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3052, Australia"},{"name":"Department of Surgery, Austin Health, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Javadrashid, D., Baghbanzadeh, A., Derakhshani, A., Leone, P., Silvestris, N., Racanelli, V., Solimando, A.G., and Baradaran, B. 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