{
  "abstract": "Tumor heterogeneity is a major determinant of tumor progression and therapeutic resistance, yet the contribution of metabolism to intratumoral heterogeneity still remains poorly explored. Here, we find that pyruvate dehydrogenase kinase-1 (Pdk1) expression defines metabolically distinct cancer cell populations in colorectal tumors. Image-based spatial single-cell phenotyping shows that Pdk1-high cells are associated with tumor progression in orthotopic models of colorectal cancer (CRC). Genetic ablation experiments demonstrate the role of Pdk1-high cells in tumor growth, 5-fluorouracil chemoresistance and tumor relapse. Mechanistically, we identify a link between Pdk1-driven metabolic states and specific cell phenotypes, where Pdk1-high cancer cells exhibit an EMT, stem cell-like phenotype characterized by increased interferon (IFN) signaling. Mitochondrial remodeling in Pdk1-high cells leads to the release of mitochondrial DNA to the cytosol and activation of IFN pathways, promoting Pdk1-driven phenotypes. Inhibition of IFN signaling impairs the tumorigenic and aggressive features of Pdk1-high cancer cells, thus establishing a functional connection between metabolic heterogeneity, cell-intrinsic IFN signaling and aggressive CRC.",
  "abstract_shown": true,
  "affiliations": [
    "University of Barcelona"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 20,
  "authors": [
    {
      "name": "J. Calviello"
    },
    {
      "name": "L. Poeltl"
    },
    {
      "name": "A. Mira"
    },
    {
      "name": "F. Spini"
    },
    {
      "name": "A. Larranaga"
    },
    {
      "name": "L. Fortuny"
    },
    {
      "name": "F. Vianello"
    },
    {
      "name": "A. Bonilla-Diaz"
    },
    {
      "name": "A. Alvarez-Munoz"
    },
    {
      "name": "G. Pazzagli"
    },
    {
      "name": "M. Serra"
    },
    {
      "name": "N. Ducano"
    },
    {
      "name": "M. Gut"
    },
    {
      "name": "E. Casals"
    },
    {
      "name": "A. Esteve-Codina"
    },
    {
      "name": "M. Liesa"
    },
    {
      "name": "L. Trusolino"
    },
    {
      "name": "A. Sapino"
    },
    {
      "affs": [
        0
      ],
      "name": "D. Sebastian"
    },
    {
      "affs": [
        0
      ],
      "name": "C. Sebastian"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5m0pjezw3n5x6.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.07.757309",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757309v1.full",
  "id": "5m0pjezw3n5x6",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757309v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "1306|Cancer, Hypoxia, and Metabolism"
    ]
  ],
  "openalex": "W7221185050",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757309v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5m0pjezw3n5x6.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:47Z",
      "native_id": "10.64898/2026.10.07.757309",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757309v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Pdk1-dependent metabolic heterogeneity promotes aggressive colorectal cancer through cell-intrinsic interferon signaling",
  "title_text": "Pdk1-dependent metabolic heterogeneity promotes aggressive colorectal cancer through cell-intrinsic interferon signaling",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:47Z",
  "url": "https://research.draconitic.com/paper/5m0pjezw3n5x6",
  "venue": "bioRxiv",
  "versions": []
}