# Project 3 - HDAC/GSK-3B/YAP signaling network in the liver metastatic microenvironment

> **NIH NIH P01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $324,370

## Abstract

ABSTRACT
Project 3 is designed to determine the roles of class I and II histone deacetylase (HDAC I/II),
glycogen synthase kinase-3β (GSK-3β), Yes-associated protein (YAP) and downstream signaling
pathways involving the macrophage-stimulating protein (MSP) and its receptor, RON (Recepteur
d'Origine Nantais) kinase, in promoting cancer metastasis in the liver. The project considers these
cancer cell pathways and the recruitment of hepatic stellate cells (HSCs) and Kupffer cells
(macrophages in the liver) to constitute a microenvironment for enhancing the growth of the
metastasis. The potential role of these pathways on cancer metastasis comes from our
observations in metastasis promotion using a new chemical entity we designed to inhibit HDAC
I/II and GSK-3β, two key enzymes that are overactivated in pancreatic, prostate and colorectal
cancer. Further, our preliminary shows roles for HDAC I/II and GSK-3β in regulating YAP, MSP,
RON and metastasis.
Based on preliminary results, we propose the following specific aims: (1) to investigate the
mechanisms by which HDAC and GSK-3β regulate YAP signaling in cancer cells to promote the
growth of metastasis in the liver; and (2) to investigate the regulation and role of YAP signaling in
HSCs for remodeling of cancer microenvironment in the liver to promote the growth of liver
metastasis. In collaboration with other projects of this Program, Project 3 will study the roles of
YAP and MSP/RON signaling in pancreatic, colon, and prostate cancers and determine the
relationship of these signals with fatty liver and high fat diet. The outcomes of this project will
significantly enhance our understanding of the mechanisms underlying the promotion of cancer
metastasis to the liver, with clear insights for application of the knowledge to the prevention and
treatment of cancer metastasis.

## Key facts

- **NIH application ID:** 10558486
- **Project number:** 5P01CA233452-04
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Stephen J. Pandol
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $324,370
- **Award type:** 5
- **Project period:** 2020-01-21 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10558486

## Citation

> US National Institutes of Health, RePORTER application 10558486, Project 3 - HDAC/GSK-3B/YAP signaling network in the liver metastatic microenvironment (5P01CA233452-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10558486. Licensed CC0.

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