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.
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.
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.
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.
Novel therapeutic strategies for KRAS-driven cancers such as pancreatic cancer have been limited by a failure to identify pathways that are specifically required in cancer cells but dispensable in normal tissues. Functionally-relevant oncofetal proteins represent ideal targets for such strategies as they are silenced during the early stages of development and in adult tissues, but may be aberrantly reactivated to drive the growth of human cancers.
Work in our laboratory studies a distinct subset of pancreatic cancer that is defined by pronounced induction of the oncofetal protein Lin28b, which is an RNA binding protein and negative regulator of the let-7 microRNA. In addition to Lin28b, many downstream Lin28b/let-7 oncofetal targets such as the RNA-binding protein insulin growth factor 2 binding proteins (IGF2BPs) and the chromatin architectural protein high mobility group AT-hook 2 (HMGA2) are also upregulated. Importantly, these oncofetal proteins are responsible for cell growth and contribute to tumor aggressiveness, as pancreatic cancer patients with high expression of LIN28B, IGF2BP3 or HMGA2 have reduced overall survival. Our laboratory uses a diverse panel of genetically-defined pancreatic cancer human and murine cell lines, mouse models and pancreatic cancer tissue microarrays to determine how oncofetal proteins become dysregulated during pancreatic cancer progression and how each protein contributes to tumorigenesis.