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Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.
Fan, Weiguo; Adebowale, Kolade; Váncza, Lóránd; Li, Yuan; Rabbi, Md Foysal; Kunimoto, Koshi; Chen, Dongning; Mozes, Gergely; Chiu, David Kung-Chun; Li, Yisi; Tao, Junyan; Wei, Yi; Adeniji, Nia; Brunsing, Ryan L; Dhanasekaran, Renumathy; Singhi, Aatur; Geller, David; Lo, Su Hao; Hodgson, Louis; Engleman, Edgar G; Charville, Gregory W; Charu, Vivek; Monga, Satdarshan P; Kim, Taeyoon; Wells, Rebecca G; Chaudhuri, Ovijit; Török, Natalie J.
Afiliação
  • Fan W; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
  • Adebowale K; VA, Palo Alto, CA, USA.
  • Váncza L; Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
  • Li Y; Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
  • Rabbi MF; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
  • Kunimoto K; VA, Palo Alto, CA, USA.
  • Chen D; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
  • Mozes G; VA, Palo Alto, CA, USA.
  • Chiu DK; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA.
  • Li Y; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
  • Tao J; VA, Palo Alto, CA, USA.
  • Wei Y; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
  • Adeniji N; VA, Palo Alto, CA, USA.
  • Brunsing RL; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
  • Dhanasekaran R; VA, Palo Alto, CA, USA.
  • Singhi A; Department of Pathology, Stanford University, Stanford, CA, USA.
  • Geller D; Division of Immunology, Stanford University, Stanford, CA, USA.
  • Lo SH; Department of Automation, Tsinghua University, Beijing, China.
  • Hodgson L; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • Engleman EG; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
  • Charville GW; VA, Palo Alto, CA, USA.
  • Charu V; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
  • Monga SP; VA, Palo Alto, CA, USA.
  • Kim T; Department of Radiology, Stanford University, Stanford, CA, USA.
  • Wells RG; Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
  • Chaudhuri O; VA, Palo Alto, CA, USA.
  • Török NJ; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Nature ; 626(7999): 635-642, 2024 Feb.
Article em En | MEDLINE | ID: mdl-38297127
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 ß-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-ß1-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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma Hepatocelular / Progressão da Doença / Elasticidade / Matriz Extracelular / Cirrose Hepática / Neoplasias Hepáticas Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Nature Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
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PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma Hepatocelular / Progressão da Doença / Elasticidade / Matriz Extracelular / Cirrose Hepática / Neoplasias Hepáticas Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Nature Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos