CAREER: Engineering biomimetic environments to elucidate mechanisms of dormancy in brain metastatic breast cancer cells

University Of Alabama Tuscaloosa, Tuscaloosa AL

Investigators

Abstract

A majority of breast cancer-related deaths worldwide occur as a result of the cancer spreading to one or more organs, often described as becoming "metastatic." Accumulating evidence suggests that cancer cells can reside in vital organs (e.g., brain) in a sleep mode (dormant) for extended periods of time and could reawaken at a later stage resulting in disease relapse and often death. However, the mechanisms by which metastatic breast cancer cells in the brain stay dormant and later become activated are not well understood, making it difficult to develop new therapeutic strategies. A few experimental models have been devised for studying dormancy in metastatic breast cancer cells; however, experimental model systems to study dormancy in brain metastatic breast cancer cells outside of a living organism (in vitro) are not available. This project focuses on developing an engineered biomimetic three dimensional in vitro experimental model of dormancy to study how biophysical, biochemical, and cellular signals of the brain tissue microenvironment regulate dormancy in brain metastatic breast cancer cells and define the associated molecular mechanisms. The technologies developed and insights gained could be broadly applied to fundamental investigations of neural development, tissue regeneration, and stem cell engineering as stem cells typically stay in a dormant state until activated to promote tissue repair, and could be used to study dormancy in other types of brain metastatic cancers. The education and outreach plans are well integrated with research and include: providing educational sessions in high schools and in a "Scientist for a Day" program, initiating a four-day mentored research experience for students and teachers from Alabama's economically challenged Black Belt region, providing research experiences for undergraduate students and enhancing undergraduate and graduate education by developing a course in cancer bioengineering and tailoring existing coursework to incorporate problems with biological relevance. These activities are designed with the goal of motivating pursuit of STEM careers for students from socially and economically challenged backgrounds, women, and minority students. The project focuses on developing an in vitro model to test the hypothesis that biophysical, biochemical and cellular cues in the brain microenvironment regulate the dormancy of breast cancer cells that have metastasized to the brain. Three dimensional (3D) tissue-mimetic hydrogel scaffolds using hyaluronic acid will be engineered to replicate biochemical composition, mechanics and cellular components of the brain. The scaffolds created will provide controllable systems to investigate microenvironment-tumor cell interactions, to study the mechanisms controlling dormancy and to test if the dormant phenotype observed in BCBM cells is reversible by modulating the scaffold environment. The Research Plan is organized under 4 specific aims: 1) Investigate the influence of mechanical cues (stiffness and mechanotransduction pathways) in regulating tumor dormancy in vitro; 2) Investigate the influence of biochemical cues (biomolecules found in the brain tumor extracellular matrix) in regulating tumor dormancy in vitro; 3) Investigate the influence of cellular cues (astrocytes) in regulating tumor dormancy in vitro and 4) Examine known signaling pathways (e.g., p38 and TGF-Beta) regulating dormancy in the biomimetic environment in vitro and identify additional pathways using a systems biology approach (proteomics and genomics), i.e., to elucidate the mechanisms governing dormancy in the engineered biomimetic scaffold, linking microenvironmental factors to the ultimate cellular phenotype: "dormant" or "proliferative." This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.