# MICROENVIRONMENTAL CONTROLS OF TUMOR DORMANCY

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $503,927

## Abstract

Bone metastasis is a key determinant of long-term survival and quality of life for breast cancer patients.
Despite the fact that the majority of breast cancer cases are diagnosed early, approximately 10-20% recur in
patients previously “cured”, demonstrating that primary disseminated tumor cells (DTCs) metastasize early and
remain dormant in distant sites only to awaken years later. Indeed, approximately 50% of patients harbor
DTCs in their bone marrow and among metastatic sites, bone metastasis is the most common site and
correlates with reduced survival and quality of life. Given the large percentage of patients who return to the
clinic years after their initial “cure”, and the sad fact that treatment options are limited or only palliative,
uncovering the mechanisms that protect dormant DTCs and allow their eventual outgrowth will have a
profound impact on the development of novel therapies and patient outcome. We have developed a novel
genetic mouse model (FASST) to spatially and temporally control the activation of senescence in
mesenchymal cells including osteoblasts in the bone. Using the FASST model, we found that the activation of
senescence led to increased expression of the protumorigenic senescence associated secretory phenotype
(SASP) in bone mesenchymal cells that drove local bone turnover and facilitated tumor DTC proliferation in the
bone. Intriguingly, we found that DTCs localized near senescent cells, raising the possibility that the niche
created by these cells drove DTCs to proliferate. Because months to years can pass between an initial
diagnosis and relapse, the fact that senescent cells increase in human tissue over this time frame and we that
find that senescent cells drive DTC proliferation, we hypothesize that activation of senescence in the bone
mesenchyme instigates emergence from dormancy and growth into overt metastatic bone lesions. To test this
hypothesis, we propose to establish the functional impact of bone turnover and SASP on dormant DTC
dynamics and determine how depletion of senescent osteoblasts impact DTC dormancy within the bone. We
will also ask how dormant DTCs interact with the bone and how this is altered upon the activation of
senescence. We will also ask if an aging immune system contributes to emergence of DTCs from dormancy.
Finally, we will carry out single cell RNA sequencing of DTCs isolated from the bone +/- activation of
senescence to determine how extrinsic signals from the bone impact DTC intrinsic pathways. Together these
approaches will poise us to develop novel therapies that target the bone stromal compartment while
simultaneously attacking entrenched DTCs.

## Key facts

- **NIH application ID:** 9897506
- **Project number:** 5R01AG059244-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sheila A Stewart
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $503,927
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897506

## Citation

> US National Institutes of Health, RePORTER application 9897506, MICROENVIRONMENTAL CONTROLS OF TUMOR DORMANCY (5R01AG059244-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9897506. Licensed CC0.

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