Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver

Weiguo Fan, Kolade Adebowale, Lóránd Váncza, Yuan Li, Md Foysal Rabbi, Koshi Kunimoto, Dongning Chen, Gergely Mozes, David Kung-Chun Chiu, Yisi Li, Junyan Tao, Yi Wei, Nia Adeniji, Ryan L. Brunsing, Renumathy Dhanasekaran, Aatur Singhi, David Geller, Su Hao Lo, Louis Hodgson, Edgar G. Engleman, Gregory W. Charville, Vivek Charu, Satdarshan P. Monga, Taeyoon Kim, Rebecca G. Wells, Ovijit Chaudhuri and Natalie J. Török ()
Additional contact information
Weiguo Fan: Stanford University
Kolade Adebowale: Stanford University
Lóránd Váncza: Stanford University
Yuan Li: Stanford University
Md Foysal Rabbi: Purdue University
Koshi Kunimoto: Stanford University
Dongning Chen: Stanford University
Gergely Mozes: Stanford University
David Kung-Chun Chiu: Stanford University
Yisi Li: Tsinghua University
Junyan Tao: University of Pittsburgh and University of Pittsburgh Medical Center
Yi Wei: Stanford University
Nia Adeniji: Stanford University
Ryan L. Brunsing: Stanford University
Renumathy Dhanasekaran: Stanford University
Aatur Singhi: University of Pittsburgh and University of Pittsburgh Medical Center
David Geller: University of Pittsburgh and University of Pittsburgh Medical Center
Su Hao Lo: University of California at Davis
Louis Hodgson: Albert Einstein College of Medicine
Edgar G. Engleman: Stanford University
Gregory W. Charville: Stanford University
Vivek Charu: Stanford University
Satdarshan P. Monga: University of Pittsburgh and University of Pittsburgh Medical Center
Taeyoon Kim: Purdue University
Rebecca G. Wells: University of Pennsylvania
Ovijit Chaudhuri: Stanford University
Natalie J. Török: Stanford University

Nature, 2024, vol. 626, issue 7999, 635-642

Abstract: Abstract Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-β1–tensin-1–YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-023-06991-9 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:626:y:2024:i:7999:d:10.1038_s41586-023-06991-9

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-06991-9

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().