Peyton:Research

Home                                                                                      Internal   

Engineered Materials to Study Mechanisms of Stem Cell Motility in Metastasis The overwhelming cause of morbidity in cancer patients is metastasis: the ability of tumor cells to mobilize, leave the primary tumor site, invade distant tissue, and launch secondary tumors. In 1889, Dr. Steven Paget analyzed data from hundreds of breast cancer fatalities and noted that metastases were most often found in a specific subset of organs, e.g. the lung and liver. In addition to the primary site, the pre-metastatic niche is also an area of inflammation, and stem cells (mesenchymal, hematopoietic, and endothelial progenitors) are recruited to this distant site before the arrival of metastatic tumor cells. These stem cells initiate the premetastatic niche by remodeling the local tissue microenvironment, altering matrix physicochemical properties, and attracting circulating tumor cells. We are using engineered materials to study this metastatic cascade of events: stem cell-tumor cell crosstalk, stem cell mobilization and ensuing adhesion, proliferation, and remodeling of the pre-metastatic tissue, and the preferential attraction of circulating tumor cells. Matrix Physicochemical Cues as Chemotherapeutic Protective Agents in Hepatocellular Carcinoma 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. As shown in the following schematic, the applicant hypothesizes 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. Signaling Network-Microenvironment Crosstalk in Metastasis 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.