2. Academic Validation
  3. ANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation

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

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. gdotto@mgh.harvard.edu.
  • 10 Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. gdotto@mgh.harvard.edu.
  • 11 ORL service, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. gdotto@mgh.harvard.edu.
  • 12 International Cancer Prevention Institute, Epalinges, Switzerland. gdotto@mgh.harvard.edu.
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.

Figures
Products