The UCI Brain Tumor Research Laboratory, established in 2006 by Mark Linskey, MD, is located in building Med Sci 1 on the UCI main campus. The basic science research laboratory is an in vitro primary and secondary cell culture and molecular biology laboratory, including real-time PCR, that also works with in vivo subcutaneous and intracranial stereotactic nude mice human brain tumor xenograft models. 

Since its inception, the team has focused on applying biological principles learned from normal neuronal-glial stem cell biology and molecular pathways to the study of human malignant glioma biology. This includes growing primary and secondary human glioma cultures and cell lines with chemically defined, serum-free media under both adherent and nonadherent spheroidal culture conditions and Matrigel cell invasion assays. 

The group has an interest in modeling patient glioma prognosis through quantitative gene expression as well as clinical outcomes data. Find out more about their study here. 

They also have a longstanding interest in the glioma biology implications of the PAX6 developmental gene pathway as a glioma tumor suppressor gene. Read more about their study here.

Chromosomal Instability of Chromosome 7 and Malignant Glioma Subpopulation Dynamics
 

An illustration showing the study of the cellular subpopulation interdynamics between the malignant glioma mass-like cell (TMC) subpopulation and the stem-like tumor initiating cell (STIC) subpopulations

The most recent major interest of the Brain Tumor Research Laboratory relates to studying the cellular subpopulation interdynamics between the malignant glioma mass-like cell (TMC) subpopulation and the stem-like tumor initiating cell (STIC) subpopulations — specifically, how these subpopulations relate to resistance to standard therapies and tumor reemergence/recurrence after standard therapies are completed. One of the team’s seminal discoveries was that bidirectional chromosomal instability (CIN) of chromosome 7, which houses the epidermal growth factor receptor (EGFR) gene, among many others, is the key to these subpopulations transitioning back and forth, leading to repopulation of the subset initially reduced by standard therapies and thus tumor recurrence. 

The group’s studies were the first to show that STICs had two copies of chromosome 7, while TMCs were aneuploid for chromosome 7, and that CIN allowed each cell subpopulation to give rise to their counterpart. 

View publications:

EFEMP1 Variant as a Novel New Malignant Glioma Therapeutic Agent
 

A close up of a glioma brain tumor

The laboratory identified EGF-containing fibulin extracellular matrix protein – 1 (EFEMP1) as a downstream signaling target of the normal developmental gene and glioma suppressor gene PAX6. EFEMP1, a normal extracellular matrix (ECM) protein in the human central nervous system, turns out to have pleiotropic effects on malignant glioma biology. It suppresses cellular division via the EGFR pathway. It suppresses neoangiogenesis via the VEGF pathway, and it suppresses the ability of the TMC population to repopulate after conventional therapies, thus suppressing eventual tumor recurrence via suppression of CIN. To eliminate its undesirable effect of promoting individual tumor SLC migration/invasion potential, the team engineered multiple EFEMP1 variants until they created one human fibulin-3 variant (hFV3v), which retained all three desirable anti-tumor effects while eliminating the undesirable individual cellular invasion-promoting effect of its parent normal gene. The protein product of hFV3v is called ZR30 and has been patented in the lab as a novel normal human protein variant with strong potential for “bench-to-bedside” therapeutic translation for treating patients with malignant gliomas.

View publications: