טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentIvanir Eran
SubjectBiosynthetic Materials for Selective 3D Migration and
Invasion of Neoplastic and Mesenchymal Cells for
Screening Cancer Drugs and
Evaluating Chemosensitivity
DepartmentDepartment of Nanoscience and Nanotechnology
Supervisor Professor Dror Seliktar


Abstract

Cell migration is one of the fundamental aspects of many physiological and path-physiological processes in the body. It has a crucial role in various events of embryogenesis, organ development and regular tissue function. Migration of different cell types can affect how the body responds to an infection, heals tissue injuries and maintains homeostasis, to name just a few. Cell migration is also prominent in cancer metastasis; tumor cells that disseminate from a primary tumor into the lymphatic and blood vessels can subsequently form new tumors in distant organs. Neoplastic or tumor cell migration is particularly important to understand in this regard, in order to develop therapeutic strategies that can limit tumor invasion or to design diagnostic tools that help identify tumor potency and chemosensitivity. In the body, migratory neoplastic cells (metastatic cells) are confined by the extracellular matrix (ECM), which is a complex 3D terrain of proteins and polysaccharides that encapsulates most tissue cells. To migrate, the cell must interact with the surrounding ECM and change its body shape and rigidity. In general, neoplastic cells migrate and invade the ECM using either an amoeboid or a mesenchymal migration mechanism. Because different neoplastic cell types use different migration and invasion mechanisms to invade their surrounding matrix (i.e. amoeboid vs. mesenchymal) one can employ a strategy whereby customized cell-specific ECM biomaterial analogs can be engineered with a set of properties that precisely control these processes. Using this approach, a material can be designed to increase the outgrowth and proliferation of one cell type while blocking the invasion of another.
Towards this goal, we used hybrid biomaterials that can initiate important cellular remodeling events, including cell migration, proliferation, and guided differentiation by balancing the structural and biofunctional elements. We applied this versatile family of the hybrid biomaterials for developing an artificial tumor growth model system that simulates tumor biopsies embedded inside biomaterial scaffolds to gain a better understanding of how the material bioactivity and matrix physical properties can independently affect cell behavior and cellular invasion. We directed the structural properties through the content of the synthetic polymer and adjusted the cellular remodeling events through the incorporation of different biological macromolecules. After we identified the dominant features of the hydrogel that can be used to selectively manipulate neoplastic cell invasion into the matrix, we tested the materials with an artificial tumor growth model and real tumors as a platform for screening anti-cancer drugs.