CCBIO seminar: Joanna J. Phillips
GBM heterogeneity and extracellular regulation of oncogenic signaling
Joanna J. Phillips
Brain Tumor Research Center, Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco (UCSF), CA, USA
Glioblastoma (GBM) is characterized by tumor heterogeneity and progression. Our laboratory is focused on understanding how tumor heterogeneity contributes to disease progression. An important component of the tumor contributing to tumor heterogeneity is the brain tumor microenvironment, including the extracellular matrix and proteoglycans. Using a combination of in vivo and ex vivo model systems and primary human biospecimens, we demonstrate that heparan sulfate (HS), on cell surfaces and in the extracellular matrix, promotes activation of multiple receptor tyrosine kinase (RTK) signaling pathways in GBM and contributes to therapeutic resistance. Within the tumor cell population, we identify a subset of glioma progenitor cells that upon targeted RTK inhibition demonstrate altered oxidative stress, with decreased lipid peroxidation and generation of toxic lipid peroxidation products. This tumor subpopulation has elevated aldehyde dehydrogenase (ALDH) levels and is more resistant to targeted RTK inhibition. Therapeutic targeting of both tumor-intrinsic and tumor-extrinsic factors, such as HS, represents potentially promising therapeutic strategies in GBM.
Chairperson: Marion Kusche-Gullberg, CCBIO