If breast cancer is detected early, it is associated with very high cure rates. Metastatic breast cancer, however, is still largely thought to be incurable. Bone is often the first site of metastasis of breast cancer, regardless of the disease subtype, and patients with bone metastases are at an increased risk of fractures, severe bone pain, and are associated with the poorest prognosis. One confounding aspect of bone metastasis is that even after apparently successful therapy, disseminated tumor cells can enter a prolonged period of dormancy before eventual reactivation and outgrowth. Dormancy is hypothesized to be a result of a lack of nutrients or pro- quiescent factors in the microenvironment at the secondary site. Some components of the microenvironment that contribute to dormancy and relapse have been identified, but many of the in vivo insights made have not been borne out in clinical data, and there are no effective treatments targeting dormancy. One major limitation in the field is that the bulk of the technologies to quantify tumor cell dormancy and outgrowth are limited to static, endpoint measurements. This is largely due to a reliance on in vivo models, which do not frequently exhibit bone metastasis, and there are obvious inherent challenges with live imaging in the bone cavity. It is therefore not currently possible to determine if observed dormant, non-proliferative cells are capable of eventual outgrowth, nor what factors from the microenvironment might coincide with that outgrowth. This is a critical barrier to progress in the field that the proposed project attempts to address. Our approach will combine in vivo models with an in vitro synthetic bone marrow to identify novel features of the bone marrow microenvironment responsible for prolonged cellular dormancy and re-activation of disseminated tumor cells. Our preliminary data suggests that the dynamic assembly and disassembly of fibronectin in the extracellular space of dormant niches is a significant modulator of dormancy. We will use this as motivation target the survival signals downstream of fibronectin binding, and degradation of fibronectin via MMP-2 to eliminate dormant disseminated cells. In addition, this in vitro hydrogel system will allow us to more broadly screen for additional, novel ECM targets that could modulate a dormant vs. proliferative phenotype more profoundly in the bone marrow space. If the proposed aims are successful, we will deliver a novel hydrogel system that mimics bone marrow, and new possible targets for treating dormancy in breast cancer.

Public Health Relevance

Some breast cancer patients can present as disease-free for years, or even decades, before recurrence. This period of remission before late relapse is called ?dormancy,? and it is unknown what factors from cells or the microenvironment can cause cells to enter and exit this dormant state. We will use engineered, controllable materials systems to uncover what these factors are.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA223783-02
Application #
9706785
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Snyderwine, Elizabeth G
Project Start
2018-07-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Massachusetts Amherst
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
153926712
City
Hadley
State
MA
Country
United States
Zip Code
01035