Glioblastoma multiforme (GBM) is the most common, aggressive, and deadly form of brain cancer (survival rate ~12 mo median; <5% after 3 yrs). Unlike other highly metastatic tumors (e.g., lung, breast), which display conserved processes of metastasis, GBM spreads diffusively through the brain via processes of invasion. Our central hypothesis is that gradients in biophysical cues and perivascular signals which exist across the margins of GBM tumors uniquely prime a sub-population of GBM cells to avoid current generation treatments. The overall goal of this supplement proposal is to develop advanced manufacturing approaches to examine proceses associated with GBM cell invasion across the GBM tumor margins within perivascular niche (PVN) zones. This proposal will elucidate mechanisms of how the tumor margins shape GBM and address the acute clinical need for biomaterial tools. The innovative strategy to be pursued involves extrusion-based 3D-bioprinting (EBB) to generate a three-dimensional GBM-laden hydrogel construct. EBB offers an unmatched capability to finely control spatial patterning of biological, biophysical, and biochemical components to create a more complex tissue-mimetic 3D construct, difficult to generate via conventional biomaterials fabrication. Selective incorporation of GBM (U87MG lines) cells into GelMA-based hydrogel bioinks with varying loadings of HA will be demonstrated. The topology and physical properties of the hydrogel-based bioinks (e.g., shear thinning, thixotropic behavior) will be adjusted to maximize bioprintability and GBM cell viability. EBB will be subsequently used to investigate the invasion response/cell migration of GBM cells across co-printed bioinks with different PVN zones. The project will first develop a GelMA-based hydrogel bioink for 3D-printing GBM cells (Aim 1). The project will subsequently employ the GelMA hydrogel platform to evaluate the role of HA molecular weight on GBM cell invasion across a perivascular gradient (Aim 2). Here, improved biomaterial mimics of the tumor margins may reveal a deeper understanding of the role played by the gradient environment in the tumor margins on GBM invasion and eventually therapeutic resistance, and may underlie a framework for identifying and validating combinations of therapeutic agents as personalized antitumor therapies. 1
Glioblastoma is the most aggressive and deadly form of brain cancer whose poor clinical outcome stems from its diffuse invasion across the tumor margins into the surrounding brain. This goal of our project is to employ additive manufacturing technologies to generate biomaterial mimics of the perivascular environment through which glioblastoma invades in the brain.
