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 Fortier; Morag Park; Riccardo Fodde; Martijn Gloerich; Fried J T Zwartkruis; Patrick Wb Derksen; Johan de Rooij

doi:10.1038/s41467-024-49230-z

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 Wb Derksen^*, Johan de Rooij^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	4866
Number of pages	17
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-49230-z
Publication status	Published - 7 Jun 2024

Keywords

Adaptor Proteins, Signal Transducing/metabolism
Animals
Breast Neoplasms/metabolism
Cell Line, Tumor
Collagen Type I/metabolism
Female
Gene Expression Regulation, Neoplastic
Humans
Mechanotransduction, Cellular
Mice
Neoplasm Invasiveness
Organoids/metabolism
Transcription Factors/metabolism
YAP-Signaling Proteins/metabolism

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Khalil, A. A., Smits, D., Haughton, P. D., Koorman, T., Jansen, K. A., Verhagen, M. P., van der Net, M., van Zwieten, K., Enserink, L., Jansen, L., El-Gammal, A. G., Visser, D., Pasolli, M., Tak, M., Westland, D., van Diest, P. J., Moelans, C. B., Roukens, M. G., Tavares, S., ... de Rooij, J. (2024). A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion. Nature Communications, 15(1), Article 4866. https://doi.org/10.1038/s41467-024-49230-z

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title = "A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion",

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.",

keywords = "Adaptor Proteins, Signal Transducing/metabolism, Animals, Breast Neoplasms/metabolism, Cell Line, Tumor, Collagen Type I/metabolism, Female, Gene Expression Regulation, Neoplastic, Humans, Mechanotransduction, Cellular, Mice, Neoplasm Invasiveness, Organoids/metabolism, Transcription Factors/metabolism, YAP-Signaling Proteins/metabolism",

author = "Khalil, {Antoine A} and Daan Smits and Haughton, {Peter D} and Thijs Koorman and Jansen, {Karin A} and Verhagen, {Mathijs P} and {van der Net}, Mirjam and {van Zwieten}, Kitty and Lotte Enserink and Lisa Jansen and El-Gammal, {Abdelrahman G} and Daan Visser and Milena Pasolli and Max Tak and Denise Westland and {van Diest}, {Paul J} and Moelans, {Cathy B} and Roukens, {M Guy} and Sandra Tavares and Anne-Marie Fortier and Morag Park and Riccardo Fodde and Martijn Gloerich and Zwartkruis, {Fried J T} and Derksen, {Patrick Wb} and {de Rooij}, Johan",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = jun,

day = "7",

doi = "10.1038/s41467-024-49230-z",

language = "English",

volume = "15",

journal = "Nature Communications",

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Khalil, AA, Smits, D, Haughton, PD, Koorman, T, Jansen, KA, Verhagen, MP, van der Net, M, van Zwieten, K, Enserink, L, Jansen, L, El-Gammal, AG, Visser, D, Pasolli, M, Tak, M, Westland, D, van Diest, PJ , Moelans, CB, Roukens, MG, Tavares, S, Fortier, A-M, Park, M, Fodde, R, Gloerich, M, Zwartkruis, FJT, Derksen, PW & de Rooij, J 2024, 'A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion', Nature Communications, vol. 15, no. 1, 4866. https://doi.org/10.1038/s41467-024-49230-z

TY - JOUR

T1 - A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion

AU - Khalil, Antoine A

AU - Smits, Daan

AU - Haughton, Peter D

AU - Koorman, Thijs

AU - Jansen, Karin A

AU - Verhagen, Mathijs P

AU - van der Net, Mirjam

AU - van Zwieten, Kitty

AU - Enserink, Lotte

AU - Jansen, Lisa

AU - El-Gammal, Abdelrahman G

AU - Visser, Daan

AU - Pasolli, Milena

AU - Tak, Max

AU - Westland, Denise

AU - van Diest, Paul J

AU - Moelans, Cathy B

AU - Roukens, M Guy

AU - Tavares, Sandra

AU - Fortier, Anne-Marie

AU - Park, Morag

AU - Fodde, Riccardo

AU - Gloerich, Martijn

AU - Zwartkruis, Fried J T

AU - Derksen, Patrick Wb

AU - de Rooij, Johan

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024/6/7

Y1 - 2024/6/7

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing/metabolism

KW - Animals

KW - Breast Neoplasms/metabolism

KW - Cell Line, Tumor

KW - Collagen Type I/metabolism

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Mechanotransduction, Cellular

KW - Mice

KW - Neoplasm Invasiveness

KW - Organoids/metabolism

KW - Transcription Factors/metabolism

KW - YAP-Signaling Proteins/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85195533905&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-49230-z

DO - 10.1038/s41467-024-49230-z

M3 - Article

C2 - 38849373

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4866

ER -

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

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Keywords

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