# Defining the impact of stromal aging on ovarian cancer initiation

> **NIH NIH U01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $457,624

## Abstract

Age is a major risk factor for high grade serous ovarian cancer (HGSOC) with an average age at diagnosis of
63. Ovulation and aging induce inflammatory changes in the fallopian tube microenvironment, the origin of most
HGSOC. Over time, cells become senescent and secrete regulatory factors known as the senescence
associated secretory phenotype (SASP). SASP-induced changes in the local microenvironment have been
implicated in cancer promotion. However, the role of the aging microenvironment in ovarian cancer initiation is
unknown creating a major barrier to effective early detection and prevention strategies for this deadly disease.
The goal of this proposal is to define the impact of aging on interactions between stromal cells and cancer
initiating cells (CIC) that drive ovarian cancer formation. Mesenchymal stromal/stem cell (MSC) are multipotent
stromal progenitor cells critical to tissue homeostasis across the lifespan. In cancer, MSCs undergo epigenomic
reprogramming to become pro-tumorigenic cancer associated MSCs (CA-MSCs). The pro-tumorigenic CA-MSC
phenotype is driven by the activation of the Wilms tumor 1 (WT1) transcription factor. WT1 induces the secretion
of CA-MSC derived BMP4 which increases the pool of ovarian CICs. Preliminary data demonstrate that with
increasing age, MSCs can express WT1 and adopt a cancer promoting phenotype even before cancer starts.
We have termed these cells ‘high risk’ MSCs (hrMSCs). Preliminary data indicate that hrMSCs (i) recapitulate
the CA-MSC phenotype and are enriched in the stroma of pre-malignant epithelial cells, (ii) secrete SASP-like
proteins which both induce epithelial cell DNA damage and support the survival of DNA damaged epithelial cells
and (iii) support established cancer cell growth. AMP-activated protein kinase (AMPK) may be critical to CA-
MSC/hrMSC formation. In a clinical trial Metformin, which increases AMPK, reversed the CA-MSC phenotype in
some patients correlating with improved survival. Preliminary data shows a more potent, novel AMPK activator,
BC1618, alters the hrMSC secretome. We hypothesize that aging induces epigenetic changes which convert
MSCs to hrMSCs and that hrMSCs create a pro-tumorigenic microenvironment that supports the growth of
ovarian CICs. Our collaborative team with expertise in aging, stromal stem cells and CICs propose to: 1)
Determine the impact of aging on the fallopian tube MSC phenotype and spatial relationship to CICs. We
hypothesize that aged MSCs obtain a high risk phenotype through altered DNA methylation and support adjacent
CIC formation. 2) Determine the impact of aged hrMSCs on CIC formation and ovarian cancer progression. We
hypothesize that aged hrMSCs promote CIC formation and progression via WT1-mediated BMP4 and SASP
secretion. 3) Target aging hrMSCs to limit ovarian cancer formation. We hypothesize that the AMPK activator,
BC1618, through altering age-related MSC epigenetic changes, will decrease hrMSC formation and ovarian
cancer initiat...

## Key facts

- **NIH application ID:** 10491889
- **Project number:** 5U01AG077923-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ronald J Buckanovich
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $457,624
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491889

## Citation

> US National Institutes of Health, RePORTER application 10491889, Defining the impact of stromal aging on ovarian cancer initiation (5U01AG077923-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10491889. Licensed CC0.

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