Project 2: Investigating cell intrinsic and extrinsic drivers of prostate cancer bone metastasis

Project Summary/Abstract
The objective of our research is to elucidate tumor cell intrinsic and extrinsic mechanisms that give rise
to bone metastasis and specify bone tropism. The foundation for our studies is the NPKYPF mouse model, which
develops highly penetrant bone metastasis that is well-conserved with bone metastasis in human prostate
cancer. Analyses of these mice enable investigations of the evolution of bone metastases during cancer
progression in the native microenvironment in androgen-intact and androgen-deprived contexts. We have found
that co-activation of MYC and RAS signaling is essential for bone metastasis, and that MYC activation is
particularly relevant in contexts of androgen deprivation. Our preliminary studies have identified ATAD2 as a
MYC-co-factor that is expressed in bone metastasis, particularly in contexts of androgen deprivation, and
necessary for bone metastasis. In a complementary genome-wide in vivo CRISPR screening based on human
prostate cancer xenografts, we identified CITED2, another MYC co-factor, as a cell-intrinsic driver of bone
metastasis that it is sufficient to promote bone metastasis in vivo. Furthermore, single cell sequencing of primary
tumors and bone metastases from NPKYPF mice has led to the identification master regulators (MRs) that are
candidate cell intrinsic drivers of bone metastasis, while analyses of the non-tumor components have shown that
primary tumors from metastatic NPKYPF mice are deficient for most immune cell populations, but highly enriched
for tumor associated macrophages.
Thus, we will investigate the hypothesis that bone metastasis represents the culmination of cell intrinsic
drivers from the metastatic cells and tumor cell extrinsic factors in microenvironment of the metastatic bone. In
Aim 1, we will investigate the hypothesis that CITED2 collaborates with MYC to promote bone specificity. In
parallel, we will investigate candidate master regulators (MRs) associated with RAS pathway activation to
elucidate their potential roles in bone metastasis. In Aim 2, we will investigate the hypothesis that ATAD2 is a
co-factor for MYC in contexts of androgen deprivation, and elucidate the relationship of androgen status for the
evolution and underlying mechanisms of bone metastasis. In Aim 3, we will investigate cell extrinsic mechanisms
in the microenvironment of the primary tumor and metastatic bone, to identify relevant cell populations associated
with metastasis, to evaluate their functional role for bone metastasis, and to identify cell extrinsic drivers of bone
metastasis.
Integration: Our studies are highly complementary to investigations of the tumor microenvironment for
neuroendocrine differentiation (Project 3) and tumor progression (Project 1). Validation of candidate regulators
for human bone metastasis will require Core A. Further, our systematic analysis of bone metastasis at the single
cell level, complement efforts in Projects 1 and 3, while our ability to mutually benefit from these data will be
enabled by the data management component of Core B.

Grant Number: 5P01CA265768-04
NIH Institute/Center: NIH
Principal Investigator: Cory Abate-Shen