{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:26:10Z","timestamp":1791300370255,"version":"4.1.0"},"reference-count":174,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T00:00:00Z","timestamp":1696464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education, Science, Sports, and Culture of Japan","award":["22K06890"],"award-info":[{"award-number":["22K06890"]}]},{"name":"Ministry of Education, Science, Sports, and Culture of Japan","award":["22K07203"],"award-info":[{"award-number":["22K07203"]}]},{"name":"Suzuken Memorial Foundation","award":["22K06890"],"award-info":[{"award-number":["22K06890"]}]},{"name":"Suzuken Memorial Foundation","award":["22K07203"],"award-info":[{"award-number":["22K07203"]}]},{"name":"Kishimoto foundation","award":["22K06890"],"award-info":[{"award-number":["22K06890"]}]},{"name":"Kishimoto foundation","award":["22K07203"],"award-info":[{"award-number":["22K07203"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite the \u201cbig data\u201d on cancer from recent breakthroughs in high-throughput technology and the development of new therapeutic modalities, it remains unclear as to how intra-tumor heterogeneity and phenotypic plasticity created by various somatic abnormalities and epigenetic and metabolic adaptations orchestrate therapy resistance, immune evasiveness, and metastatic ability. Tumors are formed by various cells, including immune cells, cancer-associated fibroblasts, and endothelial cells, and their tumor microenvironment (TME) plays a crucial role in malignant tumor progression and responses to therapy. ADP-ribosylation factor 6 (ARF6) and AMAP1 are often overexpressed in cancers, which statistically correlates with poor outcomes. The ARF6-AMAP1 pathway promotes the intracellular dynamics and cell-surface expression of various proteins. This pathway is also a major target for KRAS\/TP53 mutations to cooperatively promote malignancy in pancreatic ductal adenocarcinoma (PDAC), and is closely associated with immune evasion. Additionally, this pathway is important in angiogenesis, acidosis, and fibrosis associated with tumor malignancy in the TME, and its inhibition in PDAC cells results in therapeutic synergy with an anti-PD-1 antibody in vivo. Thus, the ARF6-based pathway affects the TME and the intrinsic function of tumors, leading to malignancy. Here, we discuss the potential mechanisms of this ARF6-based pathway in tumorigenesis, and novel therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms241914934","type":"journal-article","created":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T01:07:13Z","timestamp":1696554433000},"page":"14934","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["ADP-Ribosylation Factor 6 Pathway Acts as a Key Executor of Mesenchymal Tumor Plasticity"],"prefix":"10.3390","volume":"24","author":[{"given":"Ari","family":"Hashimoto","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/s41586-021-03822-7","article-title":"The mutational landscape of human somatic and germline cells","volume":"597","author":"Moore","year":"2021","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41586-020-1943-3","article-title":"The repertoire of mutational signatures in human cancer","volume":"578","author":"Alexandrov","year":"2020","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/s41568-018-0060-1","article-title":"The COSMIC Cancer Gene Census: Describing genetic dys-function across all human cancers","volume":"18","author":"Sondka","year":"2018","journal-title":"Nat. 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