||5R37CA227190-04 Interpret this number
||Brigham And Women'S Hospital
||Comprehensive Characterization of Prostate Stromal Gene Expression and Association with Lethal Prostate Cancer
Prostate cancer has a heterogeneous prognosis, and clinicians and researchers still lack definitive means to
distinguish potentially lethal from indolent disease. Discovery of molecular biomarkers that improve the
identification of indolent versus potentially lethal prostate cancer at diagnosis would enhance the ability to
determine which patients would benefit more from immediate treatment and those who are better served by
active surveillance. Studies of the association of gene expression with lethal prostate cancer have
predominantly focused on the tumor epithelium; however, the prostate microenvironment has drawn increasing
attention as a critical driver of cancer progression. Signaling factors from the microenvironment influence the
epithelium to acquire properties such as increased motility, proliferation, and invasive behavior. Despite these
important findings, characterization of stromal gene expression has been addressed only on a small scale. We
previously identified genes associated with prostate cancer aggressiveness using expression data from pure
laser-capture microdissected stroma from 25 radical prostatectomy specimens. We additionally have shown
that DNA alterations in prostate cancer are associated with unique transcriptional programs in epithelial tissue.
We and others have determined that several of the inherited prostate cancer risk variants function as
expression Quantitative Trait Loci in tumor and normal epithelium; however, not all risk SNPs were associated
with gene expression, possibly because the impact of genetic variants is tissue specific. We now extend these
analyses to focus on gene expression of prostate stroma. We hypothesize that (1) a gene expression signature
in stroma (alone or in combination with an epithelial gene expression signature) is predictive of prostate cancer
aggressiveness and outcome; (2) prostate cancer subtypes with distinct DNA alterations are associated with
gene expression in stroma; (3) prostate cancer risk variants are associated with stromal gene expression; and
(4) the composition of cell types within the stroma surrounding the tumor may be predictive of prostate cancer
aggressiveness and outcome. To test these hypotheses, we will perform gene expression profiling of tumor-
and normal- associated stroma for ~400 prostate cancer cases (including 115 lethal cases) with existing
epithelial gene expression data from the Physicians’ Health Study and the Health Professionals Follow-up
Study Tumor Cohort. We will also perform multiplex immunohistochemical staining of tissue microarrays
consisting of 1500 prostate cancer cases (117 lethal cases) to study stroma cell type composition. In our
project, we innovatively combine genetics, tumor and microenvironment biology, and biomarker development
using rigorous statistical and bioinformatics approaches. Focus on adjacent stromal tissue is potentially
transformative for clinical care by significantly adding to available epithelial molecular prognostic tests. An
improved understanding of the role of the microenvironment in tumor initiation and progression may also
potentially lead to the development of stroma-targeted therapies.
Multiplex Immunofluorescence in Formalin-Fixed Paraffin-Embedded Tumor Tissue to Identify Single-Cell-Level PI3K Pathway Activation.
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Clinical cancer research : an official journal of the American Association for Cancer Research, 2020-11-15; 26(22), p. 5903-5913.