# Elucidating and testing causal drivers of inflammation triggered prostatic early lesions

> **NIH NIH U54** · JOHNS HOPKINS UNIVERSITY · 2024 · $278,890

## Abstract

Project Summary/Abstract:
We have proposed that inflammatory infiltrates in human PIA reflect an anti-prostatic pro-inflammatory immune
response that serves as a hotbed for cancer initiation. Interestingly, the acute and chronic inflammatory cell
infiltrates common in PIA are generally not seen in most prostate cancers. These observations have prompted
our proving ground hypothesis which suggests that in order for prostate cancer to develop past these
initiated steps in PIA to bona fide pre-neoplastic precursor (PIN) and to invasive carcinoma, this immune
response must be abrogated. We observed upregulation of stress-response and inflammatory genes in human
PIA luminal epithelial cells. These same genes (examples: GSTP1, PTGS2, and LTF ) are epigenetically silenced
in PIN and early and metastatic invasive adenocarcinoma of the prostate. This led to a potential molecular
mechanism in which a set of genes whose expression is highly induced in PIA undergo silencing to allow cells to
emerge as PIN and invasive carcinoma. We show here that the major inflammatory mediator Stimulator of
Interferon Genes (STING) is absent in normal prostate luminal cells, is highly induced in intermediate luminal
cells in PIA, and is not expressed in the vast majority of human PIN and adenocarcinomas. We hypothesize
STING expression in PIA luminal cells is required for inflammation, cell injury, and the prostate cancer initiation.
Second, we hypothesize that in a subset of PIA cells, epigenetic silencing of STING (or of its downstream
signaling activity) results in dampening of the immune response, imparting a growth advantage by allowing them
to emerge as neoplastic cells. We will test these hypotheses in as follows. In Specific Aim 1 we will genetically
and pharmacologically test the STING activation hypothesis for developing acute and chronic inflammation, PIA
and PIN in the mouse prostate using our unique mouse model of IL1-beta induced prostatic inflammation and
PIA progressing to PIN (IMPI mice). In Specific Aim 2 we will test the “epigenetic silencing of induced genes”
hypothesis in human samples by performing a comprehensive characterization of DNA-methylation based
epigenomic changes in mouse and human epithelial cells in the transitions from prostatic inflammatory lesions to
neoplasia. Mechanistically, we hypothesize that STING (along with many other stress and inflammation induced
genes) is epigenetically silenced at the transition stage of PIA to high grade PIN. In Specific Aim 3, we
hypothesize that in "graduating" from the proving ground, neoplastic cells leave behind the pro-inflammatory
microenvironment in PIA, and sculpt a microenvironment with reduced adaptive immune cells through
recruitment of immune suppressive myeloid and lymphoid cells (e.g. MDSCs, M2 macrophages and Tregs) that
help quell the cancer immune response. We will define the cellular composition and spatial architecture of
microenvironment in mouse and human early precursor prostatic inf...

## Key facts

- **NIH application ID:** 10918239
- **Project number:** 5U54CA274370-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** ANGELO Michael DE MARZO
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $278,890
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918239

## Citation

> US National Institutes of Health, RePORTER application 10918239, Elucidating and testing causal drivers of inflammation triggered prostatic early lesions (5U54CA274370-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10918239. Licensed CC0.

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