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Peer-reviewedCC BYScience Advances

A TERRA-NONO axis drives fibroblast reprogramming in cancer

  • Emery Di Cicco1
  • Jovan Isma1,2
  • Stefano Sol1
  • Gaetana Restivo3
  • Luigi Mazzeo2
  • Atul Katarkar2
  • Sandro Goruppi1
  • Joni Renee White1
  • Juerg Hafner3
  • Victor A. Neel4
  • Anna Mandinova1
  • Mitchell P. Levesque3
1 more authors
  • Gian Paolo Dotto1,2,5
5 affiliations
  1. 1Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  2. 2Department of Immunobiology, University of Lausanne, Epalinges, Switzerland.
  3. 3Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
  4. 4Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  5. 5International Cancer Prevention Institute, Epalinges, Switzerland.
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Abstract

The molecular mechanisms linking chromosome homeostasis to fibroblast reprogramming into cancer-associated fibroblasts (CAFs) remain poorly understood. Here, we identify a clinically relevant, telomere-associated nuclear pathway driving CAF activation across multiple human cancers. The long noncoding RNA TERRA is consistently elevated in CAFs from skin, lung, and breast tumors. We show that the androgen receptor (AR) represses TERRA transcription through subtelomeric binding, and its loss enables TERRA up-regulation and interaction with the RNA binding protein NONO. This interaction forms a CAF-specific nuclear complex that reprograms gene expression. Mechanistically, NONO is directly recruited to and binds the promoters of key CAF effector genes, where it regulates their transcription in a TERRA-dependent manner. Disrupting the TERRA-NONO axis, via TERRA silencing or pharmacologic NONO inhibition, reverses CAF activation and suppresses tumor-stroma interactions in vitro and in vivo, highlighting its therapeutic potential.

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Cite

BibTeXRIS
BibTeX
@article{cicco2026terranono,
  title = {{A TERRA-NONO axis drives fibroblast reprogramming in cancer}},
  author = {Emery Di Cicco and Jovan Isma and Stefano Sol and Gaetana Restivo and Luigi Mazzeo and Atul Katarkar and Sandro Goruppi and Joni Renee White and Juerg Hafner and Victor A. Neel and Anna Mandinova and Mitchell P. Levesque and Gian Paolo Dotto},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aed3358},
  url = {https://www.science.org/doi/10.1126/sciadv.aed3358},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - A TERRA-NONO axis drives fibroblast reprogramming in cancer
AU  - Emery Di Cicco
AU  - Jovan Isma
AU  - Stefano Sol
AU  - Gaetana Restivo
AU  - Luigi Mazzeo
AU  - Atul Katarkar
AU  - Sandro Goruppi
AU  - Joni Renee White
AU  - Juerg Hafner
AU  - Victor A. Neel
AU  - Anna Mandinova
AU  - Mitchell P. Levesque
AU  - Gian Paolo Dotto
PY  - 2026
DA  - 2026/10/02
JO  - Science Advances
DO  - 10.1126/sciadv.aed3358
UR  - https://www.science.org/doi/10.1126/sciadv.aed3358
AB  - The molecular mechanisms linking chromosome homeostasis to fibroblast reprogramming into cancer-associated fibroblasts (CAFs) remain poorly understood. Here, we identify a clinically relevant, telomere-associated nuclear pathway driving CAF activation across multiple human cancers. The long noncoding RNA TERRA is consistently elevated in CAFs from skin, lung, and breast tumors. We show that the androgen receptor (AR) represses TERRA transcription through subtelomeric binding, and its loss enables TERRA up-regulation and interaction with the RNA binding protein NONO. This interaction forms a CAF-specific nuclear complex that reprograms gene expression. Mechanistically, NONO is directly recruited to and binds the promoters of key CAF effector genes, where it regulates their transcription in a TERRA-dependent manner. Disrupting the TERRA-NONO axis, via TERRA silencing or pharmacologic NONO inhibition, reverses CAF activation and suppresses tumor-stroma interactions in vitro and in vivo, highlighting its therapeutic potential.
SN  - 2375-2548
ER  -