With a dismal 5-year survival rate of ~8%, pancreatic cancer is projected to become the second leading cause
of all cancer-related deaths by 2030. While many therapeutics against pancreatic cancer have been identified,
treatment of this disease remains challenging owing to the exceptionally dense and hypovascularized stromal
tissue. Therefore, deeper understanding of tumor-stroma interactions in a viscoelastic matrix will facilitate the
identification of novel molecular targets against this deadly disease. Polymeric hydrogels capable of
recapitulating aspects of the extracellular matrix (ECM) are ideal for studying cancer cell fate as these gels can
be engineered with precise biophysical and/or biochemical properties that emulate the tumor ECM. The long-
term objective of this project is to use bio-inspired, responsive, and viscoelastic (BRAVE) matrices for elucidating
molecular mechanisms governing progression of pancreatic cancer cells (PCCs), as well as for identifying novel
molecular targets to improve treatment outcome. In this R01 project, we will develop BRAVE hydrogels
composed of functionalized hyaluronic acid and gelatin, as well as collagen and fibronectin for interrogating
matrix factors guiding pancreatic cell behaviors. In Aim 1, we will develop the said BRAVE hydrogels to define
the synergisms between major matrix components (e.g., HA, FN, and matrix viscoelasticity) on PCC progression.
In Aim 2, we will prepare BRAVE hydrogels compatible with high-content assay (HCA) of cell fate processes.
We will also design dual-layer BRAVE gels with identical biochemical compositions but spatially graded
mechanics for co-culturing PCCs and patient-derived cancer associated fibroblasts (PD-CAFs), the major tumor
stromal cells. This platform will provide direct experimental evidence regarding the necessity of a stiffened matrix
on cell-cell crosstalk and EMT in PCCs. In Aim 3, we will develop BRAVE gel with gradient stiffness to interrogate
PCC migration (i.e., durotaxis) under the influence of various matrix factors (e.g., cytokines, CAFs, and
inhibitors). The results will provide insights regarding PCC migration/invasion and potential molecular targets
against PCC metastasis. The BRAVE hydrogels and durotaxis device developed in this proposal will allow us to
answer many pancreatic cancer relevant questions that are otherwise difficult to address. Furthermore, the
outcome of this project will have impact on basic and applied research in other cancers, as well as on directed
stem cell differentiation for tissue regeneration.