{
  "abstract": "Tumor-promoting myofibroblastic carcinoma-associated fibroblasts (myCAFs) are induced by activation of transforming growth factor-{beta} signaling. However, the molecular basis of myCAF-specific transcriptional programs regulated by TGF-{beta} signaling remains poorly understood. Using a meta-analysis of single-cell RNA-seq data from 132 human breast tumor and non-tumor tissues, we show that myCAFs activate gene regulatory programs relevant to skeletal and cardiovascular development that are associated with poorer outcomes in breast cancer patients. Of note, distal-less homeobox 5 (DLX5), a master transcription factor for skeletal development, is activated in human breast myCAFs at both epigenetic and transcriptional levels. DLX5 expression is also initiated by TGF-{beta}1 treatment in human mammary fibroblasts. Immunoprecipitation and CUT&RUN assays using DLX5-expressing fibroblasts demonstrate that DLX5 interacts with Smad2/3/4 proteins, enabling their cooperative occupancy at shared genomic binding sites of target genes, thereby promoting canonical TGF-{beta} signaling and the myCAF state. DLX5-primed myCAFs also enhance paracrine TGF-{beta} signaling and neuropilin-2 expression to promote collective tumor invasion. Our findings indicate that DLX5 induces myCAF formation and promotes breast tumor progression in collaboration with canonical TGF-{beta} signaling.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pathology and Oncology, Juntendo University Faculty of Medicine"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "Y. Mezawa"
    },
    {
      "name": "K. Kumegawa"
    },
    {
      "name": "K. Morita"
    },
    {
      "name": "L. Yang"
    },
    {
      "name": "K. Hirakuri"
    },
    {
      "name": "K. Yamashita"
    },
    {
      "name": "T. Shirakihara"
    },
    {
      "name": "R. Sasaki"
    },
    {
      "name": "H. Onagi"
    },
    {
      "name": "G. Kutomi"
    },
    {
      "name": "R. Maruyama"
    },
    {
      "affs": [
        0
      ],
      "name": "A. Orimo"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d9wctjtb1zeb6.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.30.745418",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.30.745418v1.full",
  "id": "d9wctjtb1zeb6",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.30.745418v1",
  "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",
      "1312|TGF-β signaling in diseases"
    ]
  ],
  "openalex": "W7204778909",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.30.745418v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/d9wctjtb1zeb6.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:30Z",
      "native_id": "10.64898/2026.08.30.745418",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.30.745418v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Distal-less homeobox 5 gives rise to myofibroblastic carcinoma-associated fibroblasts to promote collective breast cancer invasion",
  "title_text": "Distal-less homeobox 5 gives rise to myofibroblastic carcinoma-associated fibroblasts to promote collective breast cancer invasion",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:30Z",
  "url": "https://research.draconitic.com/paper/d9wctjtb1zeb6",
  "venue": "bioRxiv",
  "versions": []
}