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Charity"},{"name":"Hodgson Family Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Colorectal cancer develops through a normal-adenoma-carcinoma sequence, yet only 5-10% of adenomas progress to malignancy, and the cellular programs governing that sequence remain poorly defined. Here we generate a spatial multi-omics atlas of human colon adenomas, combining Visium CytAssist and protein co-detection across 24 nonadvanced and advanced tubular adenomas with single-cell resolution Xenium Prime 5K profiling of 101 patient-matched normal, adenoma, and carcinoma cores from 16 patients. Integrating whole-transcriptome and 31-plex protein data identifies nine spatial clusters and two dysplastic epithelial populations that co-express stemness, proliferation, and senescence programs. These programs occupy a shared, spatially confined epithelial niche that expands from adenoma to carcinoma. Spatial analysis revealed GDF15, a senescence-associated secretory factor, mediated the coupling between senescence and stemness in advanced adenomas, and that GDF15-high epithelium locally excludes CD8+ T cells in adenoma and, more broadly, in carcinoma. These findings position senescence as a spatially instructive rather than merely tumor-suppressive program during colorectal carcinogenesis and suggest GDF15 might be a potential candidate target for cancer prevention and interception in the colon.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of Significance<\/jats:title>\n                  <jats:p>Spatial multi-omics identifies spatially co-localized senescence and stemness programs in dysplastic epithelium during colorectal tumorigenesis and links GDF15-associated niches to CD8-positive T-cell exclusion, nominating GDF15 for colorectal cancer prevention and interception strategies.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conflicts of interests<\/jats:title>\n                  <jats:p>The authors declare the following competing interests: W.M.G.: Consulting for Guardant Health, Research support from Lucid Diagnostics; E.W.N.: Co-founder, advisor, and shareholder of ImmunoScape. All the other authors declare no competing interests.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.06.743310","type":"posted-content","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:35:14Z","timestamp":1786116914000},"source":"Crossref","is-referenced-by-count":0,"title":["Spatial multi-omics and single-cell transcriptomics uncover senescence-associated cellular programs during colon adenoma to cancer progression"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8692-6135","authenticated-orcid":false,"given":"Ming","family":"Yu","sequence":"first","affiliation":[{"name":"Translational Sciences and Therapeutics, Fred Hutchinson Cancer Center, Seattle WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8716-2840","authenticated-orcid":false,"given":"Yumo","family":"Xie","sequence":"additional","affiliation":[{"name":"Translational Sciences and Therapeutics, Fred Hutchinson Cancer 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