NIH/NCI Program Project

Prostate Cancer Bone Metastasis: Biology and Targeting

PI: Leland W.K. Chung, PhD

Project 1

Molecular Mechanisms Initiating Prostate Cancer (PC) Metastasis

Study Goal:
This project will test the hypothesis that cells with metastasis-initiating cell (MIC) phenotype can recruit and reprogram bystander circulating and disseminated tumor cells (CTCs/DTCs) to participate in PC metastatic cascade.

Project Leader:
Leland W.K. Chung, PhD

Team Members:
Haiyen E. Zhau, PhD (Cedars-Sinai)
Ruoxiang Wang, PhD (Cedars-Sinai)
Gina Chia-Yi Chu, PhD (Cedars-Sinai)
Edwin Posadas, MD (Cedars-Sinai)
Xu Feng, PhD (University of Alabama at Birmingham)
Hsian-Rong Tseng, PhD (UCLA)

Project 2

Heparan Sulfate (HS) Proteoglycans in Prostate Cancer Bone Metastasis

Study Goal:
This project will investigate the interactions of the catabolic products of perlecan (PLN) destruction in the tumor microenvironment with PC cells, using both proteolytic fragments and released growth factor cargo bound to PLN HS chains.

Project Leader:
Mary C. Farach-Carson, PhD (Rice University)

Team Members:
Daniel Harrington, PhD (Rice University)
Daniel Carson, PhD (Rice University)

Project 3

Prostatic Epithelial Stromal Interactions Facilitate Bone Metastasis

Study Goal:
This project will determine if the stromal changes identified are biologically consequential to bone metastasis, if the epithelial changes observed in the prostatic tissue enable bone colonization, and if the stromal-epithelial alterations observed in model systems is found in patients with bone metastatic disease.

Project Leader:
Neil A. Bhowmick, PhD (Cedars-Sinai)

Team Members:
Isla Garraway, PhD (UCLA)

Project 4

Cholesterol Metabolism and Prostate Cancer Metastasis

Study Goal:
This project will test the hypothesis that SAFB1 loss activates a novel transcriptional program that alters lipid metabolism in a manner that elevates intratumoral cholesterol and androgenic sterols, and enhances intracrine pathways of androgen receptor activation.

Project Leader:
Michael R. Freeman, PhD (Cedars-Sinai)

Team Members:
Dolores Di Vizio, PhD (Cedars-Sinai)
Jayoung Kim, PhD (Cedars-Sinai)

Core A

Biostatistics and Bioinformatics Core

Study Goal:
This core will provide state-of-art biostatistics and bioinformatics methods and software pipelines for efficient data analysis and establish a centralized relational database system and data management structure that facilitates the entry, storage and retrieval of all data generated by the program project, and permits the controlled exchange of information across the several projects and cores.

Core Leader:
Mourad Tighiouart, PhD

Team Members:
Zhenqiu Liu, PhD (Cedars-Sinai)
Sungyong You, PhD (Cedars-Sinai)

Core B

Pathology and High-Resolution Imaging Core

Study Goal:
This core will provide well-characterized and highly annotated, archival pathological samples collected from different PC cell lines, human and animal model experimental tissue, and from routine and advanced histological procedures performed on soft and hard tissues.

Core Leader:
Majd Zayzafoon, PhD (University of Alabama at Birmingham)

Team Members:
Beatrice Knudsen, PhD
Michael S. Lewis, M.D. (Veterans Affairs West L.A. Medical Center)

This diagram illustrates the highly interactive nature of the four projects with focused attention on elucidating, at the molecular level, how PC cells develop bone homing potential. We identified that two potential cell types in the primary PC tissues, MICs and cells with megakaryocytes and osteoblasts- (MO-) mimicry phenotypes, are responsible for the initiation of PC bone metastasis. These cells were found to be activated and maintained by carcinoma-associated fibroblasts, perlecan fragments, and with these phenotypes exacerbated by cholesterol and lipid-rich environment, in response to SAFB1 loss. We studied the biology and devised rationale-based therapeutic targeting strategies for PC bone metastases using unique animal models developed by our group.