A YAP-centered Mechanotransduction Loop Drives Collective Breast Cancer Cell Invasion

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jun 7

PMID 38849373

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

The Multifaced Role of Collagen in Cancer Development and Progression.

Lo Buglio G, Lo Cicero A, Campora S, Ghersi G Int J Mol Sci. 2025; 25(24.

PMID: 39769286 PMC: 11678882. DOI: 10.3390/ijms252413523.

From ductal carcinoma in situ to invasive breast cancer: the prognostic value of the extracellular microenvironment.

Hulahan T, Angel P J Exp Clin Cancer Res. 2024; 43(1):329.

PMID: 39716322 PMC: 11664872. DOI: 10.1186/s13046-024-03236-z.

YAP enhances mitochondrial OXPHOS in tumor-infiltrating Treg through upregulating Lars2 on stiff matrix.

Bai J, Yan M, Xu Y, Wang Y, Yao Y, Jin P J Immunother Cancer. 2024; 12(11).

PMID: 39551603 PMC: 11574482. DOI: 10.1136/jitc-2024-010463.

Intra-tumoral YAP and TAZ heterogeneity drives collective NSCLC invasion that is targeted by SUMOylation inhibitor TAK-981.

Sharma R, Sharma S, Shriwas P, Mehta L, Vu A, Mouw J iScience. 2024; 27(11):111133.

PMID: 39524367 PMC: 11544388. DOI: 10.1016/j.isci.2024.111133.

YAP Signaling in Glia: Pivotal Roles in Neurological Development, Regeneration and Diseases.

Lin L, Yuan Y, Huang Z, Wang Y Neurosci Bull. 2024; 41(3):501-519.

PMID: 39503968 PMC: 11876503. DOI: 10.1007/s12264-024-01308-w.

References

Nagaharu K, Zhang X, Yoshida T, Katoh D, Hanamura N, Kozuka Y . Tenascin C induces epithelial-mesenchymal transition-like change accompanied by SRC activation and focal adhesion kinase phosphorylation in human breast cancer cells. Am J Pathol. 2011; 178(2):754-63. PMC: 3069868. DOI: 10.1016/j.ajpath.2010.10.015. View

Jansen K, Bacabac R, Piechocka I, Koenderink G . Cells actively stiffen fibrin networks by generating contractile stress. Biophys J. 2013; 105(10):2240-51. PMC: 3838739. DOI: 10.1016/j.bpj.2013.10.008. View

Alam H, Sehgal L, Kundu S, Dalal S, Vaidya M . Novel function of keratins 5 and 14 in proliferation and differentiation of stratified epithelial cells. Mol Biol Cell. 2011; 22(21):4068-78. PMC: 3204069. DOI: 10.1091/mbc.E10-08-0703. View

Fresques T, LaBarge M . <PE-AT>Contributions of Yap and Taz dysfunction to breast cancer initiation, progression, and aging-related susceptibility. Aging Cancer. 2021; 1(1-4):5-18. PMC: 7939065. DOI: 10.1002/aac2.12011. View

Schackmann R, van Amersfoort M, Haarhuis J, Vlug E, Halim V, Roodhart J . Cytosolic p120-catenin regulates growth of metastatic lobular carcinoma through Rock1-mediated anoikis resistance. J Clin Invest. 2011; 121(8):3176-88. PMC: 3148719. DOI: 10.1172/JCI41695. View

Kordek R, Potemski P, Kusinska R, Pluciennik E, Bednarek A . Basal keratin expression in breast cancer by quantification of mRNA and by immunohistochemistry. J Exp Clin Cancer Res. 2010; 29:39. PMC: 2873424. DOI: 10.1186/1756-9966-29-39. View

Koorman T, Jansen K, Khalil A, Haughton P, Visser D, Ratze M . Spatial collagen stiffening promotes collective breast cancer cell invasion by reinforcing extracellular matrix alignment. Oncogene. 2022; 41(17):2458-2469. PMC: 9033577. DOI: 10.1038/s41388-022-02258-1. View

Smits D, Khalil A . Multimodal Techniques to Study Tumor Growth, Basement Membrane Breaching, and Invasion in 3D Matrices. Methods Mol Biol. 2023; 2608:281-303. DOI: 10.1007/978-1-0716-2887-4_17. View

Ioachim E, Charchanti A, Briasoulis E, Karavasilis V, Tsanou H, Arvanitis D . Immunohistochemical expression of extracellular matrix components tenascin, fibronectin, collagen type IV and laminin in breast cancer: their prognostic value and role in tumour invasion and progression. Eur J Cancer. 2002; 38(18):2362-70. DOI: 10.1016/s0959-8049(02)00210-1. View

10.

Kural M, Billiar K . Regulating tension in three-dimensional culture environments. Exp Cell Res. 2013; 319(16):2447-59. PMC: 3876487. DOI: 10.1016/j.yexcr.2013.06.019. View

11.

Kopanska K, Alcheikh Y, Staneva R, Vignjevic D, Betz T . Tensile Forces Originating from Cancer Spheroids Facilitate Tumor Invasion. PLoS One. 2016; 11(6):e0156442. PMC: 4896628. DOI: 10.1371/journal.pone.0156442. View

12.

Wei S, Fattet L, Tsai J, Guo Y, Pai V, Majeski H . Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nat Cell Biol. 2015; 17(5):678-88. PMC: 4452027. DOI: 10.1038/ncb3157. View

13.

Gilles C, Polette M, Seiki M, Birembaut P, Thompson E . Implication of collagen type I-induced membrane-type 1-matrix metalloproteinase expression and matrix metalloproteinase-2 activation in the metastatic progression of breast carcinoma. Lab Invest. 1997; 76(5):651-60. View

14.

Acerbi I, Cassereau L, Dean I, Shi Q, Au A, Park C . Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol (Camb). 2015; 7(10):1120-34. PMC: 4593730. DOI: 10.1039/c5ib00040h. View

15.

Quinn H, Vogel R, Popp O, Mertins P, Lan L, Messerschmidt C . YAP and β-Catenin Cooperate to Drive Oncogenesis in Basal Breast Cancer. Cancer Res. 2021; 81(8):2116-2127. DOI: 10.1158/0008-5472.CAN-20-2801. View

16.

Hwang P, Brenot A, King A, Longmore G, George S . Randomly Distributed K14 Breast Tumor Cells Polarize to the Leading Edge and Guide Collective Migration in Response to Chemical and Mechanical Environmental Cues. Cancer Res. 2019; 79(8):1899-1912. PMC: 6467777. DOI: 10.1158/0008-5472.CAN-18-2828. View

17.

Grun D, Lyubimova A, Kester L, Wiebrands K, Basak O, Sasaki N . Single-cell messenger RNA sequencing reveals rare intestinal cell types. Nature. 2015; 525(7568):251-5. DOI: 10.1038/nature14966. View

18.

Kaneda A, Seike T, Danjo T, Nakajima T, Otsubo N, Yamaguchi D . The novel potent TEAD inhibitor, K-975, inhibits YAP1/TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma. Am J Cancer Res. 2021; 10(12):4399-4415. PMC: 7783735. View

19.

Kim N, Koh E, Chen X, Gumbiner B . E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc Natl Acad Sci U S A. 2011; 108(29):11930-5. PMC: 3141988. DOI: 10.1073/pnas.1103345108. View

20.

Meerbrey K, Hu G, Kessler J, Roarty K, Li M, Fang J . The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo. Proc Natl Acad Sci U S A. 2011; 108(9):3665-70. PMC: 3048138. DOI: 10.1073/pnas.1019736108. View