# Project 1- Role of fat in metastatic engraftment and expansion in the liver

> **NIH NIH P01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $359,780

## Abstract

PROJECT 1: Role of fat in metastatic engraftment and expansion in the liver
ABSTRACT
The metastasis of solid tumors to the liver may be a result of acquisition of features that enable survival within a
supportive metastatic niche. We found that the liver niche is generally not conducive to the expansion of prostate
cancer. However, feeding host mice with a high-fat diet for two weeks was sufficient to enable prostate cancer
growth in the liver. Similarly, pancreatic and colon cancer cells demonstrated greater expansion if the mice were
fed a high-fat diet versus if they were given a low-fat diet. The exposure of hepatocytes and cancer epithelial
cells to a saturated fatty acid, palmitate, was found to promote the expression of transforming growth factor-
β/bone morphogenic protein co-receptor, endoglin, as well as their ligands. We found that prostate cancer
epithelial expression of CD36, a pro-metastatic fatty acid receptor, is dependent on endoglin signaling in the
context of circulating fat. Based on these novel findings, we tested if neutralizing endoglin signaling affected liver
metastasis, and found that differential endoglin signaling in hepatocytes and cancer epithelial cells could
cooperatively contribute to liver metastasis. We hypothesize that circulating fat can convert the otherwise
metastasis-inhibitory liver microenvironment to be tumor-permissive, and that it can promote epithelial cell
survival in the liver in an endoglin-dependent manner. In Aim 1, we will define endoglin-associated changes in
the liver that enable metastatic engraftment. We will systematically determine how fat affects endoglin-mediated
expression of glutamine synthetase by hepatocytes and its effects on hepatic stellate cell activation in support
of prostate, pancreatic, and colon cancer liver engraftment. In Aim 2, we will identify the role of circulating fat on
tumor epithelial cells with regard to liver engraftment. We will explore the nature of endoglin-CD36 crosstalk in
cancer epithelial cells, and how it promotes the Yes-associated protein (YAP) signaling axis associated with
metastasis-enabling properties downstream of FOXM1. In Aim 3, we will identify the role that fatty acids have
on the expansion of tumor epithelial cells within the liver niche. We will study the liver ecosystem with signaling
interactions perpetuated by fat in hepatocytes and cancer epithelial cells. We identified that fat induces glutamine
synthesis by hepatocytes in an endoglin-dependent manner. The mechanism by which hepatocyte-derived
glutamine induces hepatic stellate cell activation and cancer epithelial differentiation will be elucidated. We will
test a reciprocal relationship between the liver and tumor epithelial cells, as fat impacts circulating cancer cells
and those disseminated to the liver.

## Key facts

- **NIH application ID:** 10558474
- **Project number:** 5P01CA233452-04
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Neil A. Bhowmick
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $359,780
- **Award type:** 5
- **Project period:** 2020-01-21 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10558474

## Citation

> US National Institutes of Health, RePORTER application 10558474, Project 1- Role of fat in metastatic engraftment and expansion in the liver (5P01CA233452-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10558474. Licensed CC0.

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