# Epigenetic plasticity in tumor initiation and evolution

> **NIH NIH DP1** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $966,868

## Abstract

Project Summary:
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.

## Key facts

- **NIH application ID:** 9987311
- **Project number:** 5DP1CA216873-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** BRADLEY Evan BERNSTEIN
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $966,868
- **Award type:** 5
- **Project period:** 2016-09-21 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987311

## Citation

> US National Institutes of Health, RePORTER application 9987311, Epigenetic plasticity in tumor initiation and evolution (5DP1CA216873-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9987311. Licensed CC0.

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