Epigenetic Reprogramming of Pancreatic Cancer

A central theme of our research group is to study how the dysregulation of chromatin modifying enzymes contributes to pancreatic cancer pathogenesis and, further, whether these pathways present liabilities that could be exploited for cancer therapy.

Although chromatin-remodeling proteins are frequently dysregulated in human cancer, little is known about how they control tumorigenesis. This question is particularly relevant given that oncogenic transformation often involves epigenetic rewiring to meet the demands of uncontrolled proliferation, survival and metastasis. An imbalance in chromatin dynamics can lead to cancer by inactivating tumor suppressors, activating oncogenes, or by reactivating pathways that inhibit differentiation or favor stem cell self-renewal.

A challenge of the next decade will be to not only chronicle the altered expression and mutations of chromatin factors but to also define the phenotypic ramifications and the epigenetic abnormalities for each in cancer. Exploring chromatin factor dysregulation in cancer also provides a tractable system to address a more fundamental question of how tumor cells evolve when epigenetic barriers are altered, what characteristics are selected for to enhance tumor cell growth and the plasticity of these tumor cells in response to environmental perturbations.

1. Pathogenesis of Pancreatic Cancer

What are the epigenetic barriers to the development and pathogenesis of pancreatic cancer? Large-scale deep sequencing has revealed that chromatin modifiers are frequently either lost or gained in pancreatic cancer. Our laboratory uses genetically engineered mouse models and patient derived cell lines to determine how some of these chromatin factors influence pancreatic cancer initiation, progression, and metastasis.

2. Tumor Cell Plasticity

How does chromatin factor dysregulation affect tumor cell plasticity? Pancreatic cancer cells are exposed to a variety of selection pressures during tumor development and progression including starvation, acidosis, hypoxia, oxidative stress, growth factor availability and exposure to cytotoxic agents. In order to survive, the pancreatic cancer cells must adapt to their specific microenvironment. Dysregulation of the epigenome may allow for the phenotypic plasticity needed to adapt to these environmental stresses. Our laboratory uses an unbiased approach by taking advantage of recent CRISPR/Cas9-based screening technology to determine which chromatin factors when lost provide a survival advantage upon deletion. Exploring how chromatin factors can influence tumor cell plasticity may identify novel vulnerabilities and help to elucidate the role of chromatin factor dysregulation in cancer.

3. The Epigenetics of Acquired Resistance

Resistance of malignant cells to chemotherapy and molecularly-targeted therapy is a major roadblock in our effort to cure cancer. Although specific resistance-conferring mutations have indeed been identified in many cancer patients demonstrating acquired drug resistance, the relative contribution of mutational and non-mutational mechanisms to drug resistance and the role of tumor cell subpopulations remain somewhat unclear. Our laboratory is interested in determining whether resistance is driven by epigenetic plasticity. Epigenetic modification occurs both during tumor development and during the acquisition of drug resistance and leads to altered expression of many hundreds of genes. How global are the acquired histone changes? Are there targets that are predictable and actionable? Do different therapies cause different epigenetic changes? The answers to these questions may help us design smarter strategies to treat resistant tumors.