Ana de Carvalho

High grade gliomas are the most prevalent and aggressive central nervous system tumors in the adult population. Despite intensive treatment comprised of surgical resection, radiation and DNA-alkylating agents, prognosis is still unfavorable due to high recurrence rate. The Hermelin Brain Tumor Center at Henry Ford Hospital in Detroit has one of the largest brain tumor biorepositories in the world, and contributed significantly to the high and lower grade glioma projects for The Cancer Genome Atlas (TCGA) initiative. Our lab has leveraged this resource to develop a panel of cancer stem-like cells from freshly resected high grade gliomas representing the main genomic abnormalities encountered in the clinic. These cells are used for in vitro studies and also to establish patient-derived orthotopic tumor xenografts in mice (PDX).  Employing next-generation DNA and RNA sequencing, among other molecular techniques, we study somatic tumor evolution, a dynamic process favoring clonal architectures beneficial to tumor growth under different selective pressures, such as therapeutic interventions and microenvironmental changes. We discovered that focal oncogene amplification in extra-chromosomal DNA happens in high frequency in these tumors, which adds a dynamic component to chromosomal elements-based tumor evolution, with significant implications for clinical management. We are using these models in preclinical studies to identify biomarkers and mechanisms of resistance to treatments currently in clinical development and to test novel therapeutic strategies. Results from studies using patient-derived models have potential to better inform future clinical trials and power precision medicine. Developmental plasticity is another characteristic leading to heterogeneity and resistance to therapy.  The presence of undifferentiated cells is a hallmark of aggressive high grade tumors, such as glioblastomas. For example, we have studied non-lineage specific mesenchymal gene expression in glioblastoma, and discovered that the "stemness" transcription factor Sox2 is not specific to cancer stem cells, as previously thought, but it regulates signaling critical to maintenance of plasticity and malignancy in differentiated glioblastoma cells.