{
  "abstract": "Colorectal cancer (CRC) has high phenotypic plasticity, but regulatory mechanisms of aberrant cell states are not well described. We investigated DNA methylation-based regulation of cancer cell-intrinsic transcriptomic heterogeneity in 1,183 multiregional primary tumor samples, liver metastases and tumor organoids. Most genes with strong methylation-transcriptomic association reflected canonical promoter hypermethylation and expression repression related to the CpG island methylator phenotype (CIMP). However, promoter hypomethylation and overexpression of APOLD1 and ELF5 identified two largely non-overlapping subgroups of canonical CIMP-negative CRCs enriched with stem-like and transit-amplifying cell states. APOLD1 tumors were further highly proliferative while ELF5 tumors were slow-cycling and associated with good survival in early-stage disease. Target genes showed patient-specific expression changes in matched primary-metastasis samples, and ELF5 aberrant metastases showed ex vivo sensitivity to putative targeting of stem cells by PI3K/mTOR inhibition, fetal de-differentiation and transition into non-canonical intestinal states. This implicates focal promoter hypomethylation in phenotypic plasticity in CRC metastasis.",
  "abstract_shown": true,
  "affiliations": [
    "Oslo University Hospital"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "L. Nunes"
    },
    {
      "name": "I. A. Eilertsen"
    },
    {
      "name": "R. Pinto"
    },
    {
      "name": "H. M. Vedeld"
    },
    {
      "name": "I. M. Bolstad"
    },
    {
      "name": "U. Saeed"
    },
    {
      "name": "O. H. Sjo"
    },
    {
      "name": "S. Yaqub"
    },
    {
      "name": "A. Nesbakken"
    },
    {
      "name": "K. Kryeziu"
    },
    {
      "name": "G. E. Lind"
    },
    {
      "name": "R. A. Lothe"
    },
    {
      "name": "A. Sveen"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e5n7am332atn3.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.04.763625",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.11.04.763625v1.full",
  "id": "e5n7am332atn3",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.11.04.763625v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "genomics"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.11.04.763625v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/e5n7am332atn3.ris",
  "sources": [
    {
      "first_seen": "2026-11-05T12:20:42Z",
      "native_id": "10.64898/2026.11.04.763625",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.11.04.763625v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:genomics",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Epigenetic reprogramming by promoter hypomethylation is linked to aberrant gene expression and transcriptomic plasticity in colorectal cancer",
  "title_text": "Epigenetic reprogramming by promoter hypomethylation is linked to aberrant gene expression and transcriptomic plasticity in colorectal cancer",
  "type": "preprint",
  "updated_at": "2026-11-07T00:20:54Z",
  "url": "https://research.draconitic.com/paper/e5n7am332atn3",
  "venue": "bioRxiv",
  "versions": []
}