(509b) Engineered Tissues to Quantify the Biology of Tumor Spread

Metastasis is the leading cause of fatality for women diagnosed with breast cancer. The most common anatomical sites of distant tumor growth include the brain, lung, liver, and bone, and it is well known that this metastatic spread in breast cancer is not random. Rather, different clinical subtypes of breast cancer exhibit unique patterns of metastatic site preference, called tissue tropism. As two examples, luminal A breast cancer spreads most aggressively to bone, whereas triple negative breast cancer shows the most homogeneous metastatic spread.  Given the physical and chemical diversity of these secondary tissue sites, we hypothesize that there is a relationship between the biophysical and biochemical properties of the tissue, and the ability of cells within a particular subtype of breast cancer to adhere, migrate, and grow at these secondary sites.

To quantify this relationship, we have created Metastatic Engineered Tissues (METs), which capture the integrin-binding properties of the secondary site tissues often recipient of breast cancer spread (brain, lung, and bone), and quantified the behavior of a range of cell lines that represent a subset of the known clinical subtypes of breast cancer, including their adhesion, polarization, motility, and proliferation. The spreading rates of MDA-MB-231s, BT549s, MCF-7s, and SkBr3s is heterogeneous, and cell polarization is the in vitro metric that best reflects the known metastatic aggression for each subtype.  To evaluate MET-specific responses in the presence of microenvironment-specific chemical perturbations, we have dosed cells with a range of integrin antibodies (β1, α2, and α6) as well as stimulated with EGF.  Cell response to EGF and integrin antibody is tissue specific, and, excitingly, this “MET sensitivity” reflects the known clinical site-specificity in human patients documented by Kennecke et al.  When the full data set is clustered, and regression is performed on migration speed and spreading rate data, strong evidence emerges that an antibody for β1 is the most promising clinical therapeutic to block metastatic spread to bone, brain, and lung tissue.

In parallel, we have generously received cells from the Massague lab that specifically home to brain, lung, and bone tissue. These cells have been serially passaged in mice, and are a subpopulation of the MDA-MB-231 parental cells.  Interestingly, the MET-specificity of these tissue-specific cell lines only emerges in the presence of EGF.  By regressing against the tissue-specific populations, MET-specific measurements, such as cell polarization on brain and spreading rate on lung, have emerged as putative predictors of tissue-specific spread. We are currently extending these studies to cells directly from patients at the UMass Medical School, and, connected with accompanied pathology reports and simple multivariable statistical modeling, our goal is to use this tropic fingerprinting to predict metastatic spread in patients, leading to patient-specific therapy, and improved patient surveillance.