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The rarity of the disease, together with the lack of mutations in the classical tumor suppressor genes and the paucity of models, has impaired our understanding of the mechanisms of progression and the cell of origin of these tumors. Due to their higher frequency, this review focuses on Gastro-Entero-Pancreatic (GEP) and Lung NENs. While recent molecular profiling has shed light on the possible cell of origin of GEP- and lung NENs, many questions remain unanswered and further studies using proper\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    models are needed, combined with the latest technologies such as single-cell and spatial sequencing and deep-learning for digital pathology. Genomic and epigenomic evidence suggests that pancreatic NENs originate from adult pancreatic cells rather than common progenitor cells; however, ultimate proof\n                    <jats:italic>in vitro<\/jats:italic>\n                    or in\n                    <jats:italic>vivo<\/jats:italic>\n                    is still lacking. Similarly, emerging molecular evidence suggests that lung NENs may have very diverse origins, encompassing most lung cell types, but much work is still needed to pinpoint their cell of origin. Further, tumors with mixed endocrine and non-endocrine composition suggest the possibility of trans-differentiation and acquisition of neuroendocrine features in different cell types. This review aims to summarize emerging insights on this topic, highlight future directions for identifying the cell of origin of NENs in these organs and explore how this knowledge may ultimately translate into clinical advances.\n                  <\/jats:p>","DOI":"10.1007\/s00428-025-04311-2","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T16:59:40Z","timestamp":1763139580000},"page":"21-32","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel concepts of cell-of origin in neuroendocrine neoplasms"],"prefix":"10.1007","volume":"488","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1721-6636","authenticated-orcid":false,"given":"Ilaria","family":"Marinoni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8142-7919","authenticated-orcid":false,"given":"Simona","family":"Avanthay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Alcala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"4311_CR1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.0589","author":"A Dasari","year":"2017","unstructured":"Dasari A, Shen C, Halperin D (2017) Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. 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