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

Luigi Mazzeo, Soumitra Ghosh, Emery Di Cicco, Jovan Isma, Daniele Tavernari, Anastasia Samarkina, Paola Ostano, Markus K. Youssef, Christian Simon and G. Paolo Dotto ()
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Luigi Mazzeo: University of Lausanne
Soumitra Ghosh: ORL service, Centre Hospitalier Universitaire Vaudois
Emery Di Cicco: Massachusetts General Hospital and Harvard Medical School
Jovan Isma: University of Lausanne
Daniele Tavernari: University of Lausanne
Anastasia Samarkina: University of Lausanne
Paola Ostano: Edo and Elvo Tempia Valenta Foundation
Markus K. Youssef: University of Lausanne
Christian Simon: ORL service, Centre Hospitalier Universitaire Vaudois
G. Paolo Dotto: University of Lausanne

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45308-w

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