{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T11:04:51Z","timestamp":1789297491061,"version":"build-2803163510"},"reference-count":387,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T00:00:00Z","timestamp":1733443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan","award":["22K06890"],"award-info":[{"award-number":["22K06890"]}]},{"name":"Grants-in-Aid from the 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":["Cancers"],"abstract":"<jats:p>Cancer has long been believed to be a genetic disease caused by the accumulation of mutations in key genes involved in cellular processes. However, recent advances in sequencing technology have demonstrated that cells with cancer driver mutations are also present in normal tissues in response to aging, environmental damage, and chronic inflammation, suggesting that not only intrinsic factors within cancer cells, but also environmental alterations are important key factors in cancer development and progression. Pancreatic cancer tissue is mostly comprised of stromal cells and immune cells. The desmoplasmic microenvironment characteristic of pancreatic cancer is hypoxic and hypotrophic. Pancreatic cancer cells may adapt to this environment by rewiring their metabolism through epigenomic changes, enhancing intrinsic plasticity, creating an acidic and immunosuppressive tumor microenvironment, and inducing noncancerous cells to become tumor-promoting. In addition, pancreatic cancer has often metastasized to local and distant sites by the time of diagnosis, suggesting that a similar mechanism is operating from the precancerous stage. Here, we review key recent findings on how pancreatic cancers acquire plasticity, undergo metabolic reprogramming, and promote immunosuppressive microenvironment formation during their evolution. Furthermore, we present the following two signaling pathways that we have identified: one based on the small G-protein ARF6 driven by KRAS\/TP53 mutations, and the other based on the RNA-binding protein Arid5a mediated by inflammatory cytokines, which promote both metabolic reprogramming and immune evasion in pancreatic cancer. Finally, the striking diversity among pancreatic cancers in the relative importance of mutational burden and the tumor microenvironment, their clinical relevance, and the potential for novel therapeutic strategies will be discussed.<\/jats:p>","DOI":"10.3390\/cancers16234094","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T09:55:20Z","timestamp":1733478920000},"page":"4094","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Plasticity and Tumor Microenvironment in Pancreatic Cancer: Genetic, Metabolic, and Immune Perspectives"],"prefix":"10.3390","volume":"16","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 060-0818, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1126\/science.959840","article-title":"The clonal evolution of tumor cell populations","volume":"194","author":"Nowell","year":"1976","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/nature09515","article-title":"Distant metastasis occurs late during the genetic evolution of pancreatic cancer","volume":"467","author":"Yachida","year":"2010","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nature12625","article-title":"The causes and consequences of genetic heterogeneity in cancer evolution","volume":"501","author":"Burrell","year":"2013","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.cell.2017.01.018","article-title":"Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future","volume":"168","author":"McGranahan","year":"2017","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/s41588-019-0566-9","article-title":"Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution","volume":"52","author":"Kim","year":"2020","journal-title":"Nat. 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