Gene activity is modulated in different cell types by the way genomic DNA is packaged into chromatin ? a process termed ?epigenetics?. Epigenetic controls are disrupted in nearly all forms of cancer, as well as in many other human diseases. This may occur through mutation of chromatin regulators, environmental exposures that alter chromatin structure, or inappropriate developmental cues. There is enormous enthusiasm for the potential of ?epigenetic therapies? to correct epigenetic defects in clinical settings. However, we currently lack coherent models or mechanistic understanding of how epigenetic defects promote tumors, or how they might be modulated in clinical intervention. The proposed project will pursue a novel, unifying model for how epigenetic lesions drive tumor initiation and evolution. We hypothesize that a key function of most epigenetic lesions is to induce plasticity, which allows pre-malignant or malignant cells to stochastically sample alternate gene regulatory programs. Cells that adopt programs that confer fitness (proliferation, tolerance, etc) are selected, and their epigenetic state maintained through cell division, giving rise to a new lineage and, ultimately, to malignant progression. Newly established technologies for profiling, monitoring and modulating epigenetic landscapes, including at single cell level, provide a unique opportunity to test this hypothesis and characterize the underlying mechanisms. We will focus initially on exemplar lesions that drive brain tumor initiation and evolution. The first exemplar is isocitrate dehydrogenase (IDH) gene mutations and associated DNA hyper-methylation, which we hypothesize cause stochastic disruption of chromatin boundaries and insulators, thereby allowing aberrant induction of oncogenes. The second exemplar is stress-induced histone demethylation, which we posit allows cancer stem cells to access primitive developmental programs and evolve drug tolerance. We will deeply characterize these exemplars by leveraging clinical specimens and experimental models, and by further innovating new technologies. We will then explore the extent to which plasticity pertains to other oncogenic lesions and to other diseases with epigenetic etiologies. In summary, the proposed study will deeply investigate mechanisms of epigenetic deregulation and plasticity in tumorigenesis. The research has potential to radically alter current views of epigenetic regulation in human disease, and thus has important biomedical implications.

Public Health Relevance

The importance of epigenetic deregulation in cancer is now well established, and epigenetic therapies are progressing rapidly in the clinic. Despite this, the field lacks coherent models for how epigenetic defects promote tumors, or how they may be addressed therapeutically. The proposed project will investigate novel mechanisms by which epigenetic defects drive tumor formation and relapse, and thus has broad implications for cancer diagnosis and therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1CA216873-03
Application #
9551573
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fingerman, Ian M
Project Start
2016-09-21
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Najm, Fadi J; Strand, Christine; Donovan, Katherine F et al. (2017) Orthologous CRISPR-Cas9 enzymes for combinatorial genetic screens. Nat Biotechnol :
Liau, Brian B; Sievers, Cem; Donohue, Laura K et al. (2017) Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance. Cell Stem Cell 20:233-246.e7
Ryan, Russell J H; Petrovic, Jelena; Rausch, Dylan M et al. (2017) A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas. Cell Rep 21:784-797
Flavahan, William A; Drier, Yotam; Liau, Brian B et al. (2016) Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529:110-4