# Matrix in pre-cirrhotic HCC

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $546,474

## Abstract

Project Summary/Abstract
Non-alcoholic steatohepatitis (NASH) is a major cause of HCC. It is clinically recognized that
HCC in NASH often arises at a pre-cirrhotic stage, however the pathomechanism of HCC in
non-cirrhotic livers is not well understood. As T2DM with poor glycemic control is an
independent risk factor for HCC it is plausible that there are distinct pathways that create a pro-
carcinogenic niche in non-cirrhotic T2DM/NASH. We showed that the accumulation of
advanced glycation end products (AGEs) in patients with T2DM/NASH and in an animal model
are key to necroinflammation and oxidative liver injury. Downregulation of the AGE clearance
receptor AGER1 accelerated AGE deposition, and correcting AGER1 in vivo improved NASH.
To study how high AGE environment creates permissive conditions for transformed cells, we
modulated diet/AGE content prior to hydrodynamic injection of hMET/mutant β-catenin: 1) High
AGE background induced an earlier and more invasive HCC, 2) AGE accumulation was linked
to significant changes in matrix dynamics-with an increase in energy dissipation or loss and
faster stress relaxation in response to a deformation - in an AGE and receptor for AGEs
(RAGE)-dependent manner, 3) Inhibiting AGE production reversed changes in matrix
viscoelasticity in vivo and lowered tumor burden. We will test the hypothesis that in non-
cirrhotic T2DM/NASH accumulation of AGEs contribute to an increase in matrix viscoelasticity
and matricellular changes creating a pro-invasive environment. Aim 1: We propose to
investigate the link between diet/AGE content, matrix viscoelasticity, sex and HCC phenotypes
and outcomes in a novel HCC model. In particular we will focus on how AGE-mediated
collagen crosslinks on specific amino acids can alter intermolecular recognition and interaction
with proteoglycans thereby affecting matrix dynamics. Aim 2: We will dissect the effects of
RAGE and AGER1 signals and AGE accumulation on matrix viscoelastic parameters and HCC
phenotypes. In Aim 3 we propose to develop a 3D hydrogel system with tunable viscoelasticity
and the impact of AGEs-modified matrix on cell behavior will be studied. Based on the RNAseq
data we will focus on the pathomechanism of how viscoelastic changes are sensed by cells, and
the key matricellular signals that confer invasive and migratory properties.
These studies will demonstrate the impact of AGEs on the liver matrix in non-cirrhotic NASH
and outline the pathomechanism for a pro-invasive environment. Defining the key matricellular
signals that drive invasion will enable us to pursue translational studied in the future.

## Key facts

- **NIH application ID:** 10809706
- **Project number:** 5R01CA277710-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Natalie J. Torok
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $546,474
- **Award type:** 5
- **Project period:** 2023-03-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809706

## Citation

> US National Institutes of Health, RePORTER application 10809706, Matrix in pre-cirrhotic HCC (5R01CA277710-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10809706. Licensed CC0.

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