A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion

Antoine A. Khalil (), Daan Smits, Peter D. Haughton, Thijs Koorman, Karin A. Jansen, Mathijs P. Verhagen, Mirjam Net, Kitty Zwieten, Lotte Enserink, Lisa Jansen, Abdelrahman G. El-Gammal, Daan Visser, Milena Pasolli, Max Tak, Denise Westland, Paul J. Diest, Cathy B. Moelans, M. Guy Roukens, Sandra Tavares, Anne-Marie Fortier, Morag Park, Riccardo Fodde, Martijn Gloerich, Fried. J. T. Zwartkruis, Patrick WB. Derksen () and Johan Rooij ()
Additional contact information
Antoine A. Khalil: University Medical Center Utrecht
Daan Smits: University Medical Center Utrecht
Peter D. Haughton: University Medical Center Utrecht
Thijs Koorman: University Medical Center Utrecht
Karin A. Jansen: University Medical Center Utrecht
Mathijs P. Verhagen: Erasmus Medical Center
Mirjam Net: University Medical Center Utrecht
Kitty Zwieten: University Medical Center Utrecht
Lotte Enserink: University Medical Center Utrecht
Lisa Jansen: University Medical Center Utrecht
Abdelrahman G. El-Gammal: University Medical Center Utrecht
Daan Visser: University Medical Center Utrecht
Milena Pasolli: University Medical Center Utrecht
Max Tak: University Medical Center Utrecht
Denise Westland: University Medical Center Utrecht
Paul J. Diest: University Medical Center Utrecht
Cathy B. Moelans: University Medical Center Utrecht
M. Guy Roukens: University Medical Center Utrecht
Sandra Tavares: Universidade do Porto
Anne-Marie Fortier: Goodman Cancer Institute
Morag Park: Goodman Cancer Institute
Riccardo Fodde: Erasmus Medical Center
Martijn Gloerich: University Medical Center Utrecht
Fried. J. T. Zwartkruis: University Medical Center Utrecht
Patrick WB. Derksen: University Medical Center Utrecht
Johan Rooij: University Medical Center Utrecht

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Dense and aligned Collagen I fibers are associated with collective cancer invasion led by protrusive tumor cells, leader cells. In some breast tumors, a population of cancer cells (basal-like cells) maintain several epithelial characteristics and express the myoepithelial/basal cell marker Keratin 14 (K14). Emergence of leader cells and K14 expression are regarded as interconnected events triggered by Collagen I, however the underlying mechanisms remain unknown. Using breast carcinoma organoids, we show that Collagen I drives a force-dependent loop, specifically in basal-like cancer cells. The feed-forward loop is centered around the mechanotransducer Yap and independent of K14 expression. Yap promotes a transcriptional program that enhances Collagen I alignment and tension, which further activates Yap. Active Yap is detected in invading breast cancer cells in patients and required for collective invasion in 3D Collagen I and in the mammary fat pad of mice. Our work uncovers an essential function for Yap in leader cell selection during collective cancer invasion.

Date: 2024
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DOI: 10.1038/s41467-024-49230-z

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