Mentoring: Artem Berezovsky
Oncology and Pharmacology
- Patient-derived models of glioma
- Tumor evolution, mechanisms of resistance to therapy, target validation, and combination therapies for high grade glioma
- Developmental programs aberrantly activated in high grade gliomas as key drivers of plasticity, transient cancer stem cell phenotype and drug resistance
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.
Complete list of published work here.
deCarvalho AC*, Kim H, Poisson LM, Winn ME, Mueller C, Cherba D, Koeman J, Seth S, Protopopov A, Felicella M, Zheng S, Multani A, Jiang Y, Zhang J, Nam DH, Petricoin EF, Chin L, Mikkelsen T, Verhaak RGW*. Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma. Nature Genetics 2018;50:708 – 17.
Shimada K, Reznik E, Stokes ME, Krishnamoorthy L, Bos PH, Song Y, Quartararo CE, Pagano NC, Carpizo DR, deCarvalho AC, Lo DC, Stockwell BR. Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells. Cell Chemical Biology 2018;25:585-94.
Irtenkauf SM, Sobiechowski S, Hasselbach LA, Nelson KK, Transou AD, Carlton ET, Mikkelsen T, deCarvalho AC*. Optimization of glioblastoma mouse orthotopic xenograft models for translational research. Comparative Medicine 2017;67:300-14.
Lubanska D, Market-Velker BA, deCarvalho AC, Mikkelsen T, Silva EF, Porter LA. The Cyclin-Like Protein Spy1 Regulates Growth and Division Characteristics of the CD133+ Population in Human Glioma. Cancer Cell 2014;25:64-76.
Berezovsky AD, Poisson LM, Cherba D, Webb CP, Transou AD, Lemke NW, Hong X, Hasselbach LA, Irtenkauf SM, Mikkelsen T, deCarvalho AC*. Sox2 promotes malignancy in glioblastoma by regulating plasticity and astrocytic differentiation. Neoplasia 2014;16:193-206 COVER ARTICLE
Hasselbach LA, Irtenkauf SM, Lemke NW, Nelson KK, Berezovsky AD, Carlton ET, Transou AD, Mikkelsen T, deCarvalho AC* Optimization of high grade glioma cell culture from surgical specimens for use in clinically relevant animal models and 3D immunocytochemistry. Journal of Visualized Experiments 2014;83:e51088.
deCarvalho AC*, Lehman NL, Mikkelsen T*. Overview of Molecular Signal Transduction of Malignant Gliomas and Correlation with Responses to Targeted Therapy. Current Signal Transduction Therapy 2013;8: 3-13.
deCarvalho AC*, Nelson K, Lemke N, Lehman NL, Arbab AS, Kalkanis SN, Mikkelsen T*. Gliosarcoma Stem Cells Undergo Glial and Mesenchymal Differentiation In Vivo. Stem Cells 2010;28:181–90.
Complete list of published work here.
Education/TrainingPhD (2001), Florida State University, Tallahassee, FL
CB7300 Functional Genomics and Bioinformatics
CB7243 Principles of Cancer Therapy
CB7700 Recent Developments in Cancer Biology