# Microenvironmental drivers of indolent to aggressive prostate cancer switch mediated by combined MYC Activation and PTEN loss

> **NIH NIH U54** · JOHNS HOPKINS UNIVERSITY · 2022 · $335,337

## Abstract

Project Summary/Abstract:
There is a critical need to understand the pathogenesis of aggressive vs indolent prostate cancer. The
combination of PTEN loss and MYC copy number gain predicts poor outcome in prostate cancer. Moreover,
PTEN loss, even in low grade lesions, can indicate the presence of high grade aggressive prostate cancer. We
found a synergistic interaction in driving aggressive prostatic adenocarcinoma by combining Pten loss with MYC
overexpression in a mouse model (BMPC mice). However, the molecular mechanisms by which MYC and PTEN
cooperate in driving aggressive disease are not known. We hypothesize that the combination stimulates a cell
non-autonomous immune evasion mechanism through recruitment of immunosuppressive myeloid cells and
cancer associated fibroblasts. We additionally hypothesize that these microenvironmental alterations
accompanying progression to aggressive cancer with PTEN loss may have already been conditioned in PIA
lesions within the proving ground from which these neoplastic cells initially emerged. These hypotheses are
based on strong preliminary data and prior reports indicating that: i) the chemokine Cxcl5 is upregulated upon
Pten deletion in prostate cancer precursors with high aggressive potential (BMPC PIN), and are associated with
recruitment of polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) and with increased M2
macrophages in BMPC invasive cancers; ii) these increases in myeloid cells in BMPC cancers parallel
observations of increased M2 macrophages in high grade human prostate cancer and in association with PTEN
loss; iii) aggressive human prostate cancer lesions with PTEN loss and in BMPC animals often harbor a reactive
stroma, which is correlated with FAP expression, and which has been implicated as a driver of
immunosuppression and cancer cell invasion; and iv) expression of CXCL5, and of FAP in the stroma, is
associated with a subset of PIA lesions, suggesting that these features may already be conditioned in the PIA
proving ground and reawakened during progression to aggressive disease with PTEN loss. In Aim 1, we
hypothesize that Pten loss in BMPC PIN precursors leads to induction of the chemokine Cxcl5, which recruit
PMN-MDSC and M2 macrophages to engender an immunosuppressive phenotype. In our preliminary data, we
observed an association with FAP-positive reactive stroma in the vicinity of PTEN-lost human prostate cancer.
Furthermore, FAP was upregulated in aggressive cancers from BMPC mice. In Aim 2, we will determine the role
of reactive stroma and FAP in mediating immune evasion and aggressive prostate cancer in BMPC mice. In
Aim 3, we hypothesize that the types of changes seen with PTEN loss, including FAP activation and CXCL5
upregulation, and myeloid cell infiltration, were already conditioned to occur during “graduation” of the neoplastic
cells from the PIA proving ground. Thus, we will define the epithelial and microenvironmental alterations
associated with PTEN loss in ...

## Key facts

- **NIH application ID:** 10518917
- **Project number:** 1U54CA274370-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Srinivasan Yegnasubramanian
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $335,337
- **Award type:** 1
- **Project period:** 2022-09-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518917

## Citation

> US National Institutes of Health, RePORTER application 10518917, Microenvironmental drivers of indolent to aggressive prostate cancer switch mediated by combined MYC Activation and PTEN loss (1U54CA274370-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10518917. Licensed CC0.

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