{
  "abstract": "Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, in part due to a dense and highly plastic tumor microenvironment dominated by cancer-associated fibroblasts (CAFs). In previous work, we identified a CAF population expressing a neural-associated NES+SOX4+NOTCH1+ program that increased with disease progression. The signals driving this state and the mechanisms regulating it remained unclear. Here, we investigated how tumor-derived signals activate this program and whether it represents a stable fibroblast identity or a reversible state. Using spatial transcriptomic data spanning normal pancreas to invasive carcinoma, we identified EGF, FGF2 and BDNF as candidate tumor-to-fibroblast signals associated with disease progression. Functional experiments in patient-derived CAFs and human fibroblast cell lines showed that EGF and FGF2 are sufficient to induce the NES+SOX4+NOTCH1+ program. Growth factor withdrawal reversed the NES+SOX4+NOTCH1+ program at both the protein and transcriptional levels, indicating that this state is dynamic and environment dependent. Single-cell transcriptomic analysis further revealed a multi-phase response involving early loss of fibroblast-associated features, transient activation of neural-associated genes, and a later stress-associated state. Regulatory analyses identified ETS-family transcription factors as key regulators of the program, while phosphoproteomic profiling and inhibitor studies showed that MAPK/ERK signaling plays a central role in its transcriptional activation. Finally, pan-cancer single-cell analysis showed that this state is enriched in CAFs and increases from normal to tumor tissue across multiple cancer types. Together, these findings define a reversible, growth factor-driven CAF program and identify signaling mechanisms that may provide opportunities to selectively modulate tumor-supportive fibroblast states.",
  "abstract_shown": true,
  "affiliations": [
    "Institute for Research in Immunology and Cancer, Université de Montréal"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "M. I. Ibanez-Rios"
    },
    {
      "name": "M. Batardiere"
    },
    {
      "name": "E. Dianati"
    },
    {
      "name": "G. Serwe"
    },
    {
      "name": "S. Kanagasingam"
    },
    {
      "name": "A. Archambault-Marsan"
    },
    {
      "name": "P. Thibault"
    },
    {
      "name": "M. Therrien"
    },
    {
      "name": "V. Q.-H. Trinh"
    },
    {
      "affs": [
        0
      ],
      "name": "D. J. Knapp"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2d494rdz122xd.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.07.757165",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757165v1.full",
  "id": "2d494rdz122xd",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757165v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2730|Pancreatic and Hepatic Oncology Research"
    ]
  ],
  "openalex": "W7221190732",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757165v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2d494rdz122xd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:48Z",
      "native_id": "10.64898/2026.10.07.757165",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.07.757165v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Tumour-stroma signaling drives a reversible program with neural-like features in cancer-associated fibroblasts",
  "title_text": "Tumour-stroma signaling drives a reversible program with neural-like features in cancer-associated fibroblasts",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:48Z",
  "url": "https://research.draconitic.com/paper/2d494rdz122xd",
  "venue": "bioRxiv",
  "versions": []
}