Matrix Physicochemical Cues as Chemotherapeutic Protective Agents in Hepatocellular Carcinoma
Thuy Nguyen
It has been widely accepted that inflammatory environments within the liver contain robust changes in matrix protein synthesis and matrix stiffness; however, it remains elusive as to whether or not alterations in these physicochemical properties of the ECM are causative in HCC cell phenotype. This is a critical question, as chemotherapies are traditionally screened in in vitro scenarios that do not contain these physiological properties. We plan to: 1) Determine the role of relevant adhesive matrix proteins in regulating the phenotype of HCC cell lines of varying pre-determined differentiated states; 2) Use engineered biomaterial platforms with tunable stiffness and adhesive ligand density alongside an FDA-approved kinase inhibitor to determine the role of these matrix physicochemical cues in protecting HCC cells from apoptosis; 3) Determine the intracellular signaling mechanism responsible for translating these matrix cues into chemotherapeutic protection. We hypothesize that the physicochemical properties of the ECM (matrix stiffness and ligand identity/density) act as cues to drive HCC signaling pathways. Intracellular signaling pathways activated from these cues may conflict with the kinase activity of the chemotherapeutic, providing a protection from apoptosis.
Inflammatory Feedback Loops in Cardiovascular Disease
Will Herrick
Cardiovascular disease has been the number one killer in the United States since 1900 for every year except one, and will be responsible for 37% of all deaths in the U.S. this year alone. Arteriosclerosis is defined by hardening of the arteries: a general term for arterial wall thickening and loss of elasticity. Matrix properties in atherosclerotic arteries, such as the existence of macrophages and cytokines from atherosclerotic plaques, arterial wall elasticity, and the portfolio of insoluble adhesive proteins, are altered in the onset of cardiovascular disease. Coincident with these matrix changes, smooth muscle cells (SMCs) are observed to undergo phenotypic dedifferentiation, described by gene transcription, motility/invasion, and matrix degradation/production. We are investigating the ability of matrix state to trigger SMC motility and invasion via a specific signaling network. With a novel set of tools, including biomaterials and a small shRNA library coding for genes important to SMC differentiation and motility, we can control both of the inputs to this hypothesized feedback loop. This research will generate synthetic engineered arterial mimics in which to study the biophysical crosstalk between SMCs and the chemical and physical microenvironment. These studies will lead to identification of druggable signaling nodes, to regulate SMC phenotype in patients with atherosclerosis.
Signaling Network-Microenvironment Crosstalk in Metastasis
Collaboration with the Shannon Alford Lab at the University of Minnesota
Erinn Dandley
Metastasis is the leading cause of fatality for women diagnosed with breast cancer. While specific genetic signatures have been correlated with metastatic potential, and, in some cases, prediction of metastatic tissue site, there exists no biophysical explanation for metastatic site determination. Increasing evidence suggests that the physicochemical factors within the extracellular milieu may regulate tumor growth, morphology, and tumor cell motility. The overwhelmingly complex nature of the tumor microenvironment in vivo, which includes numerous extracellular matrix proteins, cell types, inflammatory chemokines, and proteolytic enzymes, presents a significant challenge in parsing the role of physicochemical cues involved in regulating metastasis. There exists a critical need for novel in vitro experimental systems that can mimic the metastatic niche in a well-defined, controllable, and reproducible manner. We are developing novel biomaterials to systematically measure breast cancer metastasis in response to physiologically relevant physiochemical cues. We are employing mathematical modeling tools to both describe and predict the relationship between physicochemical cues of the metastatic site and the predetermined signaling network within metastatic breast cancer cell lines. Within the scope of this project, we will identify components of intracellular signaling pathways involved in metastatic site preference. These pathways could serve as checkpoints for pharmaceutical intervention, and, in the long term, control of breast cancer metastasis.
Anomalous Diffusion Methods to Predict 3D Stem Cell Motility in Porous Scaffolds
Collaboration with Joshua Cohen and the Lauffenburger Lab at Massachusetts Institute of Technology
Jaclyn Somadelis
Design of 3D scaffolds that can facilitate proper survival, proliferation, and differentiation of stem cells is a challenge for clinical applications involving large connective tissue defects. Cell migration within such scaffolds is a critical process governing tissue integration. We are currently using mathematical modeling techniques based on anomalous diffusion parameters to connect the effects of scaffold pore diameter, in concert with matrix stiffness and adhesivity, as independently tunable parameters to marrow-derived stem cell invasion into 3D synthetic scaffolds.
