Current Research
Cancer
Malignant gliomas are tumors that arise from astrocyte cells within the brain. Glioblastoma is the grade of of glioma with the worst prognosis for patient outcome. Median survival time for patients diagnosed with glioblastoma is X years. Our lab is currently investigating new ways of diagnosing and treating glioblastoma. (Wen and Kesari 2008).
Glioblastoma multiforme are tumors that arise from astrocyte cyells within the brain. Median survival time is 15 months despite advances in surgical techniques, radiation and chemotherapy(1). After treatment, nearly all gliomas recur due to the ability of individual glioblastoma tumor cells to spread from the tumor and infiltrate the surrounding normal tissue. This prevents complete removal of the tumor and contributes to a high rate of recurrence(2). Much of our current research on glioblastomas is focused on reducing the invasiveness of tumor cells
Movement is fundamental to biology. Tumor cells are remarkably small in comparison to the distance they travel when invading normal tissues. High levels of mechanical output from each individual cell are necessary to travel these long distances. Conformational changes in single molecules of the cytoskeleton lead to cellular migration within the organism. We study how GFAP, an intermediate filament found in astrocytes, is involved in that mechanical work by studying the mechanical properties of GFAP itself using single molecule force spectroscopy. We also study how the mechanical properties of whole tumor cells correlate to the invasiveness of individual tumors, and ultimately patient outcome.
1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
2. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med 2008;359:492-507.
Single Molecule Force Spectroscopy for Studying Tumor Cell Motility
Tumor cell invasion is largely a mechanical process – a cell must use its cytoskeleton to crawl through the surrounding tissue matrix. We use single molecule force spectroscopy [SMFS – link] to study the mechanical stability of molecules involved in tumor cell motility. Some of the molecules we study are found intracellularly, such as the tumor cytoskeletal protein GFAP. We also use SMFS to study molecules that comprise the brain’s extracellular matrix, such as the proteoglycan Brevican and the polysaccharide Hyaluronic Acid. These studies will allow us to develop a comprehensive, molecular-scale model for the mechanical rules that govern tumor cell invasion in the brain.
Quantitation of glioma cell motility on engineered polystyrene substrates
We have cultured tumor derived glioblastoma cells on engineered polystyrene substrates created by our collaborators at Nanotech West. The engineered substrates have lanes divided by short walls which constrain the movement of the cells to 1 dimension, which allows the movement to be accurately quantitated. We are investigating the velocity of glioblastoma cells on these devices, with the goal to correlate velocity to aggressiveness of the tumor and patient outcome for diagnostic purposes.
Evaluation of a 3D brain mimetic to evaluate the effect of extracellular matrix on glioma cell migration
Current 2D migration models do not recapitulate the mechanical environment of the ECM in the brain. 3D culture materials are believed to most closely mimic in vivo conditions. Most 3D models currently available are comprised of matierals that are not physiologically relevant in the brain (e.g., Matrigel). Our collaborators are developing a 3D hydrogel as a brain tissue mimetic for the evaluation of new 3D migration assays. We have tumor derived glioblastoma cells which are cultured within the 3D hydrogel and evaluated for migration in the presence of ECM components and in response to mechanical changes in the gel.
Multifunctional nanoparticles for aiding in preoperative and intraoperative tumor identification
Diagnosis and treatment of tumors would be greatly aided if our ability to identify tumor cells was enhanced. We are currently working with our collaborators in the Winter Lab [link] to develop a multifunctional nanoparticle that enhances tumor cell identification both before and during surgery. The nanoparticle will contain a superparamagnetic iron oxide contrast agent for use with MRI imaging, which will aid in preoperative tumor identification(3). The nanoparticle will also contain a biocompatible fluorescent particle that glows when excited by a particular wavelength of light, allowing tumor cells to be identified intraoperatively(4). The development of a device that incorporates both of these ideas will directly improve neurosurgical treatment of brain tumors.
3. Runge VM, Pels Rijcken TH, Davidoff A, Wells JW, Stark DD. Contrast-enhanced MR imaging of the liver. J Magn Reson Imaging. 1994 May-Jun;4(3):281-9.
4. Choi J, Burns AA, Williams RM, Zhou Z, Flesken-Nikitin A et. al. Core-shell silica nanoparticles as fluorescent labels for nanomedicine. J Biomed Opt. 2007 Nov-Dec;12(6):064007.