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 van der Net, Kitty van Zwieten, Lotte Enserink, Lisa Jansen, Abdelrahman G. El-Gammal, Daan Visser, Milena Pasolli, Max Tak, Denise Westland, Paul J. van Diest, Cathy B. Moelans, M. Guy Roukens, Sandra Tavares, Anne Marie FortierMorag Park, Riccardo Fodde, Martijn Gloerich, Fried J.T. Zwartkruis, Patrick W.B. Derksen*, Johan de Rooij*

*Corresponding author for this work

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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.

Original languageEnglish
Article number4866
JournalNature Communications
Issue number1
Publication statusPublished - 7 Jun 2024

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