{
  "abstract": "Pancreatic ductal adenocarcinoma (PDAC) progression is driven by a poorly understood continuum of plastic malignant cell states between the “classical” (GATA6⁺) and “basal-like” (KRT17⁺) subtypes. Here, we integrate \\(\\:scRNA\\text{-}seq\\) with quantitative proteomics from laser-capture microdissected patient tissue and targeted mechanistic perturbations to establish a framework that simplifies this continuum and defines malignant programs linked to tumor progression, metastasis, and therapy resistance. We identify a transcriptionally and proteomically distinct KRT17⁺/GATA6⁺ hybrid cell state. Spatial analyses show that hybrid cells are enriched among de-differentiating populations, concentrate at the invasive front of primary tumors, and are significantly overrepresented in lethal liver and lung metastases, indicating that this plastic phenotype is selected during the metastatic cascade. Proteomic deconstruction reveals that the hybrid state is governed by a MYC-driven oncogenic program coupled to a metabolic shift toward oxidative phosphorylation. By individually reducing KRT17 and GATA6 expression, we establish a direct KRT17→c-MYC regulatory axis that promotes broad resistance to standard therapies while creating a specific, targetable vulnerability to MYC inhibition. Together, these findings identify the KRT17⁺/GATA6⁺ hybrid phenotype as a key node of PDAC aggressiveness and therapeutic resistance and support the use of KRT17/GATA6 as biomarkers to stratify patients for clinical trials of MYC inhibitors.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 25,
  "authors": [
    {
      "name": "Lyanne Delgado",
      "orcid": "0009-0007-7662-2817"
    },
    {
      "name": "Andrew Resnick"
    },
    {
      "name": "Jonathan Ogata"
    },
    {
      "name": "Jorge Villar-Samaniego"
    },
    {
      "name": "Qian Lin"
    },
    {
      "name": "Michael Horowitz"
    },
    {
      "name": "Thomas Beggs"
    },
    {
      "name": "Tristan Kwai"
    },
    {
      "name": "Anastasia Terbaci"
    },
    {
      "name": "Kayla Schwartz"
    },
    {
      "name": "Jeremy Loffredo"
    },
    {
      "name": "Katlin Wilson"
    },
    {
      "name": "Nicholas W. Bateman"
    },
    {
      "name": "Kelly A. Conrads"
    },
    {
      "name": "Jacky D. Lin"
    },
    {
      "name": "Anika Porwal"
    },
    {
      "name": "Fjord Deda"
    },
    {
      "name": "Bo Chen"
    },
    {
      "name": "Sruthi Babu"
    },
    {
      "name": "Natalia Marchenko"
    },
    {
      "name": "Emanuel F. Petricoin III"
    },
    {
      "name": "Thomas P. Conrads"
    },
    {
      "name": "Scott Powers"
    },
    {
      "name": "Luisa Escobar-Hoyos"
    },
    {
      "name": "Kenneth Shroyer"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/eqegrz8wpfpdk.bib",
  "cited_by": 0,
  "doi": "10.21203/rs.3.rs-11519779/v1",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13734278/",
  "id": "eqegrz8wpfpdk",
  "issns": [
    "2693-5015"
  ],
  "landing_url": "https://doi.org/10.21203/rs.3.rs-11519779/v1",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2730|Pancreatic and Hepatic Oncology Research"
    ]
  ],
  "openalex": "W7225053754",
  "pdf_url": "https://www.researchsquare.com/article/rs-11519779/latest.pdf",
  "pmcid": "PMC13734278",
  "pmid": "42990812",
  "published": "2026-11-01",
  "publisher": "American Journal Experts",
  "ris": "https://research.draconitic.com/paper/eqegrz8wpfpdk.ris",
  "sources": [
    {
      "first_seen": "2026-11-08T12:23:53Z",
      "native_id": "PMC13734278",
      "source": "pmc",
      "url": "https://doi.org/10.21203/rs.3.rs-11519779/v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Pancreatic and Hepatic Oncology Research",
      "subfield": "oncology"
    }
  ],
  "title": "A KRT17/GATA6 hybrid state marks unique vulnerability to MYC in pancreatic cancer",
  "title_text": "A KRT17/GATA6 hybrid state marks unique vulnerability to MYC in pancreatic cancer",
  "type": "preprint",
  "updated_at": "2026-11-08T12:23:53Z",
  "url": "https://research.draconitic.com/paper/eqegrz8wpfpdk",
  "venue": "Research Square",
  "versions": []
}