{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:24:07Z","timestamp":1787822647796,"version":"build-2784847793"},"reference-count":141,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Neuroendocrine neoplasms (NENs) are biologically heterogeneous tumors in which differentiation\/grade and hormonal functionality are intersecting but non-equivalent axes. This review focuses on functional and non-functional well-differentiated neuroendocrine tumors (NETs), principally gastroenteropancreatic and pancreatic NETs, and critically evaluates how site, lineage, stage, tumor burden, genomic and epigenetic alterations, immune-stromal remodeling, metabolic adaptation, microbiome-associated signals, and treatment pressure converge on metastasis and recurrence. Apparent outcome differences by functionality are inconsistent after clinicopathological adjustment: non-functional presentation is often enriched for delayed diagnosis and adverse features, whereas functional subtypes range from typically indolent insulinomas to clinically aggressive hormone-producing tumors. We reconcile these observations through a layered model in which lineage-defining alterations and chromatin\/telomere programs establish cellular state; signaling and metabolic plasticity enable stress adaptation; and hypoxia, angiogenesis, immune cells, fibroblasts, extracellular matrix, and therapy create selective niches for dissemination and relapse. We also define computational strategies for heterogeneous multi-omics integration and a staged biomarker-validation pathway. Evidence remains dominated by pancreatic NETs, and causal support is weakest for microbiome-functionality relationships and several proposed cross-omic links. A spectrum-based framework is therefore most useful when it generates testable, site- and grade-specific hypotheses rather than treating functionality as an isolated prognostic variable.<\/jats:p>","DOI":"10.3389\/fendo.2026.1782791","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:15:42Z","timestamp":1787822142000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The metastatic spectrum in functional and non-functional NENs: mechanistic insights from multi-omics"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhengjian","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]},{"name":"Shandong Provincial Hospital, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuda","family":"Ji","sequence":"additional","affiliation":[{"name":"Shandong Provincial Hospital, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunzhen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangfeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Shandong Provincial Hospital 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