# Project 2 - Fatty Liver Predisposes to Metastasis: Role of Hepatic Stellate Cells

> **NIH NIH P01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $313,104

## Abstract

PROJECT 2: Fatty Liver Predisposes to Metastasis: Role of Hepatic Stellate Cells
PROJECT SUMMARY
The central hypothesis being tested by this Program project is that the normal liver has defense mechanisms
to suppress metastatic growth, which are lowered by insults to the liver microenvironment to allow metastatic
engraftment and expansion. Project 2 focuses on the role of fatty liver in liver metastasis, examining the
hypothesis that non-alcoholic fatty liver disease (NAFLD) associates with a tumor-promoting liver
microenvironment that is mediated by hepatic stellate cells (HSCs), hyaluronic acids (HAs), and hepatocyte-
derived extracellular vesicles (EVs). Obesity and NAFLD are serious health concerns that increase the risk of
primary cancers including liver, pancreas, colon, prostate, and breast. Fatty liver also supports liver metastasis
in patients as well as in rodent models. The liver is the most frequent site for metastasis of visceral cancers
such as colorectal (CRC) and pancreatic ductal adenocarcinoma (PDAC). The extent of liver metastasis is a
major survival determinant for patients with these cancers as well as for those with prostate cancer (PCa). The
objective of Project 2, thus, is to investigate molecular mechanism(s) underlying HSC-mediated, enhanced
metastatic growth in the fatty liver environment.
In liver, HSCs are precursors of liver myofibroblasts that produce extracellular matrix (ECM) components, such
as HAs. Both HSCs and the ECM are elemental in supporting a liver tumor microenvironment. This research
team's preliminary data show that HSC infiltration and ECM production (as evidenced by HAs) in metastatic
tumors were increased in a fatty liver environment. In contrast to previous studies showing that primary tumor-
derived EVs travel to the liver to create a pre-metastatic niche, we propose the innovative hypothesis that a
pro-metastatic liver microenvironment is instead facilitated by non-cancerous, steatotic hepatocytes that
secrete EVs containing pro-fibrogenic and oncogenic microRNAs (miRNAs).
This project will examine liver metastasis in fatty liver for three different cancer types (CRC, PDAC, and PCa)
via three specific aims. Aim 1 will investigate whether HSC-derived HA promotes metastatic liver tumor growth
in fatty liver with HSC-specific deletion or overexpression of HA synthase 2 (Has2), in the presence of high-fat
diet (HFD). Aim 2 will investigate whether HA overexpression in fatty liver promotes metastatic tumor growth
via CD44, Notch1, and Yes-associated protein (YAP). Aim 3 will investigate whether fatty liver-derived EVs
promote cancer metastasis to the liver by activating tumor-promoting pathways via oncogenic miRNAs. We will
also seek EV-miRNAs as biomarkers to predict patients at high risk for liver metastasis. This project integrates
with others in the Program by examining associations between fatty liver-mediated HAS2 overexpression and
YAP (Projects 1, 3) and methionine adenosyltransferase 1A (MAT1...

## Key facts

- **NIH application ID:** 10558481
- **Project number:** 5P01CA233452-04
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** EKIHIRO SEKI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $313,104
- **Award type:** 5
- **Project period:** 2020-01-21 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10558481

## Citation

> US National Institutes of Health, RePORTER application 10558481, Project 2 - Fatty Liver Predisposes to Metastasis: Role of Hepatic Stellate Cells (5P01CA233452-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10558481. Licensed CC0.

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