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; Natalie J Török

doi:10.1038/s41586-023-06991-9

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

Nature. 2024 Feb;626(7999):635-642. doi: 10.1038/s41586-023-06991-9. Epub 2024 Jan 31.

Authors

Weiguo Fan^{1

2}, Kolade Adebowale^#^{3

4}, Lóránd Váncza^#^{1

2}, Yuan Li^{1

2}, Md Foysal Rabbi⁵, Koshi Kunimoto^{1

2}, Dongning Chen^{1

2}, Gergely Mozes^{1

2}, David Kung-Chun Chiu^{6

7}, Yisi Li⁸, Junyan Tao⁹, Yi Wei^{1

2}, Nia Adeniji^{1

2}, Ryan L Brunsing¹⁰, Renumathy Dhanasekaran^{1

2}, Aatur Singhi⁹, David Geller⁹, Su Hao Lo¹¹, Louis Hodgson¹², Edgar G Engleman^{6

7}, Gregory W Charville⁶, Vivek Charu^{6

13}, Satdarshan P Monga⁹, Taeyoon Kim^{5

14}, Rebecca G Wells¹⁵, Ovijit Chaudhuri^{4

16}, Natalie J Török^{17

18}

Affiliations

¹ Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
² VA, Palo Alto, CA, USA.
³ Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
⁴ Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
⁵ Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA.
⁶ Department of Pathology, Stanford University, Stanford, CA, USA.
⁷ Division of Immunology, Stanford University, Stanford, CA, USA.
⁸ Department of Automation, Tsinghua University, Beijing, China.
⁹ Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
¹⁰ Department of Radiology, Stanford University, Stanford, CA, USA.
¹¹ Department of Biochemistry and Molecular Medicine, University of California at Davis, Sacramento, CA, USA.
¹² Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, NY, USA.
¹³ Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁴ Faculty of Science and Technology, Keio University, Yokohama, Japan.
¹⁵ Departments of Medicine and Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Department of Mechanical Engineering, Stanford University, Stanford, CA, USA.
¹⁷ Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. ntorok@stanford.edu.
¹⁸ VA, Palo Alto, CA, USA. ntorok@stanford.edu.

^# Contributed equally.

Abstract

Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development^1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions^3,4. 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.

MeSH terms

Animals
Carcinoma, Hepatocellular* / complications
Carcinoma, Hepatocellular* / metabolism
Carcinoma, Hepatocellular* / pathology
Cell Proliferation
Collagen / chemistry
Collagen / metabolism
Computer Simulation
Diabetes Mellitus, Type 2 / complications
Diabetes Mellitus, Type 2 / metabolism
Disease Progression*
Elasticity*
Extracellular Matrix* / metabolism
Glycation End Products, Advanced / metabolism
Humans
Integrin beta1 / metabolism
Liver Cirrhosis* / complications
Liver Cirrhosis* / metabolism
Liver Cirrhosis* / pathology
Liver Neoplasms* / complications
Liver Neoplasms* / metabolism
Liver Neoplasms* / pathology
Neoplasm Invasiveness
Viscosity
YAP-Signaling Proteins / metabolism
beta Catenin / metabolism

Substances

beta Catenin
Collagen
Glycation End Products, Advanced
Integrin beta1
TNS1 protein, human
YAP-Signaling Proteins
AGER protein, human

Abstract

MeSH terms

Substances

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