About the Lab
Chromatin regulators are frequently mutated in cancer, and aberrant patterns of DNA and histone modifications discriminate tumor cells from healthy tissue, suggesting that chromatin dysregulation plays a key role in tumorigenesis. Our current research focus is on pediatric high grade glioma (pHGG) driven by histone mutations including H3G34R mutations observed hemispheric tumors and H3K27M mutations seen in diffuse intrinsic pontine glioma (DIPG). Research in the Anastas lab centers on the hypothesis that disrupted chromatin regulation driven by these histone mutations gives rise to clinically-relevant cancer phenotypes including, stem and progenitor-like and drug resistant tumor cell subpopulations.
The overall goals of the lab are to determine how chromatin dysregulation drives cancer progression and the development of drug resistance on a mechanistic level, and to leverage this knowledge to develop new therapies. Future studies will address three primary questions:
- Which chromatin pathways are necessary for pHGG growth and what mechanisms drive these dependencies?
- What is the role of chromatin regulation in the development of therapeutic resistance, and can we rationally co-target the epigenome in combination with other drugs to achieve lasting disease control?
- What are the roles of epigenetic regulators in the maintenance or establishment of pHGG stem and progenitor-like cells, and how do these chromatin pathways contribute to tumor heterogeneity?
Lab Projects
During Dr. Anastas, Jamie's postdoc training she generated data showing that a novel, dual LSD1/HDAC inhibitor called Corin reduces the growth of H3K27M mutant DIPG tumors (Anastas et al, Cancer Cell, 2019). One of the lab’s main goals will be to follow up on this work to optimize combinations of LSD1 and HDAC inhibitors already available for immediate clinical use in immunocompetent mouse models of pediatric brain tumors. The initial stages of the project will involve testing LSD1/HDAC inhibitor combinations against a panel of brain tumor models to assess which tumor subtypes are responsive. Based on previous data suggesting that co-targeting LSD1 and HDACs induces a neuronal-like phenotype in glioma cells, a second component of the project will be to determine the effects of these drugs on chromatin regulation in stem-like brain tumor cells versus more differentiated tumor sub-populations.
Cancer cells require high levels of RNAPII-dependent transcription to sustain their rapid growth, which is induced, in part, by chromatin dysregulation. We have identified components of the transcription elongation machinery including, Elongin B (ELOB) in chromatin-focused CRISPR screens for pathways driving H3K27M mutant diffuse intrinsic pontine glioma (DIPG) growth. Follow-up studies confirm that knockout of ELOB reduces the growth of DIPG xenografts and that ELOB is overexpressed in tumors compared to normal brain, suggesting that ELOB is a driver of DIPG tumorigenesis. Ongoing studies are focused on understanding how specific regulators of the RNAPII transcriptional machinery, like ELOB affect H3K27M-dependent chromatin dysregulation, and at determining how aberrant activity of transcriptional regulators promotes DIPG tumorigenesis and progression.
Targeted inhibitors like the HDAC inhibitor, panobinostat and the ClpP/DRD2-targeting drug, ONC201 are currently in clinical trials for pediatric high grade glioma (pHGG), yet their efficacy is not yet know. Very little is known about the activity of chromatin regulatory pathways in pHGG cells that are either inherently insensitive to various drugs, or in pHGG that have developed resistance to chronic drug treatment. Additional studies in the lab will be aimed at identifying epigenetic markers and functional drivers of drug resistance in pHGG and applying this knowledge towards the development of novel combination therapies.
Lab Publications
Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG.
Anastas, J.N., Zee, B.M., Kalin, J.H., Kim, M., Guo, R., Alexandrescu, S., Blanco, M.A., Giera, S., Gillespie, S.M., Das, J., et al. (2019). Cancer Cell. 36(5), 528-544.
RACK7 recognizes H3.3G34R mutation to suppress expression of MHC class II complex components and their delivery pathway in pediatric glioblastoma.
Jiao, F., Li, Z., He, C., Xu, W., Yang, G., Liu, T, Shen, H., Cai, J., Anastas, J.N., Mao, Y., Yu, Y., Lan, F., Geno, Y., Jones, C., Xu, Y., Baker, S.J.*, Shi, Y.*, Guo, R.*. (2020) Science Advances. 17;6(29):eaba2113. doi: 10.1126/sciadv.aba2113.
WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors.
Anastas, J.N., Kulikauskas, R.M., Tamir, T., Rizos, H., Long, G.V., von Euw, E.M., Yang, P.-T., Chen, H.-W., Haydu, L., Toroni, R.A., et al. (2014). J. Clin. Invest. 124(7):2877-90.doi: 10.1172/JCI70156.
A protein complex of SCRIB, NOS1AP and VANGL1 regulates cell polarity and migration, and is associated with breast cancer progression.
Anastas, J.N., Biechele, T.L., Robitaille, M., Muster, J., Allison, K.H., Angers, S., and Moon, R.T. (2011). Oncogene. 31(32):3696-708.
WLS inhibits melanoma cell proliferation through the β-catenin signalling pathway and induces spontaneous metastasis.
Yang, P.-T., Anastas, J.N., Toroni, R.A., Shinohara, M.M., Goodson, J.M., Bosserhoff, A.K., Chien, A.J., and Moon, R.T. (2012). EMBO Mol. Med. 4, 1294–1307.
Mindbomb 1, an E3 ubiquitin ligase, forms a complex with RYK to activate Wnt/β-catenin signaling.
Berndt, J.D., Aoyagi, A., Yang, P., Anastas, J.N., Tang, L., and Moon, R.T. (2011). J. Cell Biol. 194, 737–750.
New regulators of Wnt/beta-catenin signaling revealed by integrative molecular screening.
Berndt, J.D., Aoyagi, A., Yang, P., Anastas, J.N., Tang, L., and Moon, R.T. (2011). J. Cell Biol. 194, 737–750.
Histone Serotonylation: Can the Brain Have “Happy” Chromatin?
Anastas, J.N., and Shi, Y. (2019). Molecular Cell. 74, 418–420.
Histone Lysine Demethylase Inhibitors.
Jambhekar, A., Anastas, J.N., and Shi, Y. (2017). Cold Spring Harb. Perspect. Med. 7.
Functional crosstalk between WNT signaling and tyrosine kinase signaling in cancer.
Anastas, J.N. (2016). Seminars in Oncology, Vol 42, No 6, December 2015, pp 820-831. Semin. Oncol. 43, 526.
WNT signalling pathways as therapeutic targets in cancer.
Anastas, J.N., and Moon, R.T. (2013). Nat. Rev. Cancer 13, 11–26.
Lab Members
