{
  "abstract": "BackgroundInflammatory bowel disease (IBD) has been linked to a two- to eightfold increase in colorectal cancer (CRC) risk. However, particular genes that bridge intestinal dysbiosis and oncogenic transcriptional reprogramming remain unclear. The Hippo/YAP pathway is a major regulator of intestinal epithelial homeostasis whose effector YAP is hyperactivated in CRC, but its transcriptional engagement in IBD mucosa and its link to specific cancer-risk genes has not been thoroughly mapped.\n\nMethodsBulk RNA-seq data were integrated from two independent cohorts: GSE235236 (IBD colon mucosa; UC/CD vs. healthy controls; n = 56) and TCGA-COAD/READ (CRC tumors stratified by YAP activity; n = 592). Differential expression analysis was conducted separately within each cohort using Welchs t-test with Benjamini-Hochberg FDR correction. YAP transcriptional activity was estimated per sample as the mean row-wise Z-score of seven canonical YAP target genes, and TCGA tumors were stratified into Hippo-High (Q4) and Hippo-Low (Q1) groups. Genes showing consistent dysregulation across both cohorts were identified and ranked to define a Dysbiosis-Hippo Response (DHR) module, which was further organized into functional gene archetypes.\n\nResultsIBD mucosa showed 2,848 significantly dysregulated genes (FDR < 0.05). Comparison with the CRC cohort identified 120 genes showing concordant dysregulation, forming the DHR module. These genes were significantly enriched in TNF-alpha signaling via NF-kB (adjusted p = 0.006), inflammatory response (adjusted p = 0.013), and Myogenesis (adjusted p = 0.013). DHR gene classification revealed three functional archetypes: (i) innate immune activation (SPI1, OSM, IL11, LILRA2, SLC11A1) reflecting convergent myeloid reprogramming; (ii) epithelial-mesenchymal transition (TWIST1, SNAI1, PRRX2, MMP9) priming invasive potential before malignancy; and (iii) tumor microenvironment immune regulation (TN-FRSF4, TNFRSF18, PDCD1, VASN, SPON2) shaping immune tolerance. Interestingly, the canonical YAP target genes (CTGF, CYR61, ANKRD1, AMOTL2, and FSTL1), sharply upregulated in Hippo-High CRC, were essentially unchanged in IBD mucosa. This signifies that the shared DHR programme operates through non-canonical YAP effectors. And yet, YAP target scores are positively correlated with DHR module expression across IBD samples (Spearman rho = 0.726, p = 2.5 x 10-10).\n\nConclusionsOur findings define a three-archetype DHR module that links gut dysbiosis to YAP-driven oncogenesis at single-gene resolution. The programme shared between IBD and CRC is driven by innate immune activation, EMT priming, and remodeling of the immune microenvironment, not by the canonical CTGF/CYR61 YAP target axis, which appears only at the CRC stage. This gene-level framework provides tractable mechanistic targets for chemoprevention and biomarker development at the inflammation-to-cancer transition.",
  "abstract_shown": true,
  "affiliations": [
    "Comsats University Islamabad, Pakistan"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "S. Noor"
    },
    {
      "name": "K. S. Vignaish"
    },
    {
      "name": "P. Joshi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/63c5n646k8b95.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.24.26363887",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.24.26363887v1.full",
  "id": "63c5n646k8b95",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.24.26363887v1",
  "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": [
    [
      "medrxiv",
      "gastroenterology"
    ],
    [
      "openalex",
      "1307|Hippo pathway signaling and YAP/TAZ"
    ]
  ],
  "openalex": "W7214431296",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.24.26363887v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-24",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/63c5n646k8b95.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:29Z",
      "native_id": "10.64898/2026.09.24.26363887",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.24.26363887v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1307|Hippo pathway signaling and YAP/TAZ",
      "subfield": "cell-biology"
    }
  ],
  "title": "Identification of Transcriptional Hippo Response Signature Connecting Inflammatory Bowel Disease and Colorectal Cancer Progression",
  "title_text": "Identification of Transcriptional Hippo Response Signature Connecting Inflammatory Bowel Disease and Colorectal Cancer Progression",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:29Z",
  "url": "https://research.draconitic.com/paper/63c5n646k8b95",
  "venue": "medRxiv",
  "versions": []
}