{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T19:11:36Z","timestamp":1782846696232,"version":"3.54.5"},"reference-count":62,"publisher":"American Society for Clinical Investigation","issue":"13","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":41,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DK082889,P01CA295524"],"award-info":[{"award-number":["R01DK082889,P01CA295524"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009863","name":"Neuroendocrine Tumor Research Foundation","doi-asserted-by":"crossref","award":["Peterson Accelerator Award"],"award-info":[{"award-number":["Peterson Accelerator Award"]}],"id":[{"id":"10.13039\/100009863","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:p>\n                    Cancers reflect aberrant growth and differentiation of normal cell populations. Biological understanding of small intestine neuroendocrine tumors (SI-NETs) is hampered because their closest normal counterparts, enteroendocrine cells (EECs), constitute tiny fractions of intestinal epithelium. Recent characterization of adult human EEC ontogeny from intestinal stem cells can help overcome that limitation. Transient expression of the transcription factor gene\n                    <jats:italic>ASCL1<\/jats:italic>\n                    normally ensures proper timing and fidelity of well-differentiated EECs, which express\n                    <jats:italic>NEUROD1<\/jats:italic>\n                    . Here, we report that SI-NETs resembled mature enterochromaffin cells; however, individual tumor cells coexpressed stem\/progenitor genes, harboring each differentiation state along the EEC trajectory except\n                    <jats:italic>\n                      ASCL1\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    precursors. We found that enhancers normally active, and others inactive, during EEC differentiation underlie aberrant SI-NET gene activity. SI-NETs uniformly expressed NEUROD1 but lacked ASCL1, owing to inaccessible chromatin and repressive H3K27me3 marking at the\n                    <jats:italic>ASCL1<\/jats:italic>\n                    locus. Multiple cyclin-dependent kinase inhibitor (CDKi) genes were similarly silenced, other than\n                    <jats:italic>CDKN1B<\/jats:italic>\n                    , the only gene recurrently mutated in SI-NETs. Deletion of\n                    <jats:italic>CDKN1B<\/jats:italic>\n                    altered cell cycle kinetics during human EEC differentiation, and deletions of ASCL1 or CDKN1B activated certain genes that are expressed in SI-NETs but not in the normal EEC trajectory. We propose that a limited CDKi repertoire and absence of ASCL1-dependent constraints on EEC maturation together explain unique SI-NET characteristics.\n                  <\/jats:p>","DOI":"10.1172\/jci197772","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T17:00:12Z","timestamp":1779382812000},"source":"Crossref","is-referenced-by-count":0,"title":["Multiomic analyses delineate human neuroendocrine tumor cell states in relation to normal enteroendocrine cell ontogeny"],"prefix":"10.1172","volume":"136","author":[{"given":"Pratik N.P.","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Medical Oncology and"},{"name":"Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa 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