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.

Public Health Relevance

Age is a significant risk factor for the development of cancer. We recently found that senescent or ?old? cells can stimulate tumor cell growth. Thus we suggest that as these ?old? cells, which we know accumulate in the bone with age, can push a dormant breast cancer cell to proliferate, leading to the formation of metastasis in the bone. We will explore how ?old? cells accomplish this and ask if we can target these processes to keep a dormant breast cancer cell ?asleep? in the bone and thus reduce breast cancer recurrence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG059244-01
Application #
9512125
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Kerr, Candace L
Project Start
2018-07-01
Project End
2023-03-31
Budget Start
2018-07-01
Budget End
2019-03-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130