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Here, we investigated cell-cell communication during serous endometrial carcinoma (SEC; also known as uterine serous carcinoma) development using a lineage-traceable mouse model and cross-species analyses of the mouse and human neoplastic endometrium. In mice, the early, pre-dysplastic stage was marked by a global decrease in inferred cell-cell interactions, followed by extensive communication network rewiring during neoplastic progression. Pathway-specific analysis revealed a similar pattern for NOTCH signaling, with NOTCH2 emerging as the dominant NOTCH receptor in\n                  <jats:italic>Trp53<\/jats:italic>\n                  \/\n                  <jats:italic>Rb1<\/jats:italic>\n                  -mutant immature epithelial cells. Functionally, NOTCH2 promoted the outgrowth of more proliferative mutant organoids. Cross-species transcriptomic analysis identified conserved immature epithelial states in mouse and human neoplastic endometrial epithelium. In human tissues, NOTCH2 was overexpressed in serous endometrial intraepithelial carcinoma, a precursor of SEC, and in overt SEC. Furthermore, elevated NOTCH2 expression was associated with poor patient survival. These findings link cell-cell communication rewiring during experimental SEC development to conserved neoplastic epithelial states and identify NOTCH2 as an early marker and a potential target of disease interception.\n                <\/jats:p>","DOI":"10.64898\/2026.09.01.748540","type":"posted-content","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T09:35:15Z","timestamp":1788428115000},"source":"Crossref","is-referenced-by-count":0,"title":["Cross-species analysis links cell-cell communication rewiring to NOTCH2 during serous endometrial carcinogenesis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5668-3061","authenticated-orcid":false,"given":"Matalin G.","family":"Pirtz","sequence":"first","affiliation":[{"name":"Department of Biomedical and Translational Sciences"},{"name":"Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, 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