Project Summary
Breast cancer (BC) is the most frequently diagnosed cancer in women. In addition, metastatic BC has a 5-year
survival rate of only 27% and metastases are associated with the vast majority of cancer-related deaths. Recent
research has highlighted a complex dynamic between cancer cells and the tumor microenvironment as essential
for the formation of macrometastases. Within this field, tissue stiffening through matrix accumulation and altered
matrix organization were recently linked with sustained proliferation and increased migration of tumor cells.
Elevated levels of the glycoprotein fibronectin (FN) have been correlated to poor patient survival in BC and are
linked to enhanced seeding of disseminated tumor cells at metastatic sites. My previous work has indicated
several mechanisms through which accumulated FN impacts the metastatic potential of BC cells. Foremost, I
helped identify a transient increase in extracellular FN in the lungs, which peaked before overt metastasis,
coupled with a non-transient increase in total lung volume. I further found that cyclic mechanical force acted as
a suppressor of cancer cell growth in a biomimetic lung model, implicating the accumulation of extracellular
matrix (ECM) as an attempt by the cancer cells to alter the mechanical properties of the lung tissue and resist
entering dormancy. However, my results showed that BC cells could not organize FN into ECM independently.
Instead, BC cells altered the accumulation and architecture of FN by conditioning resident fibroblasts through
soluble factors and extracellular vesicles. I observed that the FN produced by conditioned fibroblasts varied not
only based on the phenotype of the BC cell, but also from the method of conditioning which tested paracrine and
endocrine signaling. These preliminary results indicate that unique subtypes of cancer associated fibroblasts
(CAFs) may develop based on the BC cell conditioning mechanism, where unique subtypes may be associated
with the specific needs of the various stages of the metastatic cascade. Therefore, Aim 1 of the proposed studies
during my Ph.D. research will define the contribution of cyclic strain on BC cell phenotype and dormancy using
our novel actuating platform. Aim 2, which I will undertake during my postdoctoral research, will seek to better
define the varied roles of CAFs in metastatic progression through the development of a foundation of subtypes
after conditioning with media, isolated extracellular vesicles, and contact from BC cancer cells, including
metastatic and non-metastatic BC cells with epithelial and mesenchymal phenotypes. These findings will enable
advanced interaction studies and promote the development of novel targets for fibroblasts, which may be a more
consistent target than genetically unstable cancer cells and lead to more effective treatment. In addition, the
proposed studies and training plan will expand my current tissue engineering skillset to include advanced
understanding of mechanotransduction pathways and CAF formation as well as improve my communication,
mentoring, and teaching. Together, these skills will place me as a competitive candidate for an independent
principle investigator position in a research university at the intersection of cancer biology and engineering.