ANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation

  • Nat Commun. 2024 Feb 3;15(1):1038. doi: 10.1038/s41467-024-45308-w.
Luigi Mazzeo  1  2 ,  Soumitra Ghosh  3 ,  Emery Di Cicco  2 ,  Jovan Isma  1 ,  Daniele Tavernari  4  5  6 ,  Anastasia Samarkina  1 ,  Paola Ostano  7 ,  Markus K Youssef  1 ,  Christian Simon  3  8 ,  G Paolo Dotto  9  10  11  12
Affiliations
  • 1. Department of Immunobiology, University of Lausanne, Epalinges, Switzerland.
  • 2. Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
  • 3. ORL service, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
  • 4. Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
  • 5. Swiss Cancer Center Léman, Lausanne, Switzerland.
  • 6. Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • 7. Cancer Genomics Laboratory, Edo and Elvo Tempia Valenta Foundation, Biella, 13900, Italy.
  • 8. International Cancer Prevention Institute, Epalinges, Switzerland.
  • 9. Department of Immunobiology, University of Lausanne, Epalinges, Switzerland. [email protected].
  • 10. Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. [email protected].
  • 11. ORL service, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. [email protected].
  • 12. International Cancer Prevention Institute, Epalinges, Switzerland. [email protected].
PMID: 38310103 DOI: 10.1038/s41467-024-45308-w
Abstract

There are significant commonalities among several pathologies involving fibroblasts, ranging from auto-immune diseases to fibrosis and Cancer. Early steps in Cancer development and progression are closely linked to fibroblast senescence and transformation into tumor-promoting cancer-associated fibroblasts (CAFs), suppressed by the Androgen Receptor (AR). Here, we identify ANKRD1 as a mesenchymal-specific transcriptional coregulator under direct AR negative control in human dermal fibroblasts (HDFs) and a key driver of CAF conversion, independent of cellular senescence. ANKRD1 expression in CAFs is associated with poor survival in HNSCC, lung, and cervical SCC patients, and controls a specific gene expression program of myofibroblast CAFs (my-CAFs). ANKRD1 binds to the regulatory region of my-CAF effector genes in concert with AP-1 transcription factors, and promotes c-Jun and FOS association. Targeting ANKRD1 disrupts AP-1 complex formation, reverses CAF activation, and blocks the pro-tumorigenic properties of CAFs in an orthotopic skin Cancer model. ANKRD1 thus represents a target for fibroblast-directed therapy in Cancer and potentially beyond.

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