Transcription Factor Circuitries in Ovarian Cancer
Characterizing the lncRNA Landscape of Ovarian Cancer
Very little is known about the role of long noncoding RNAs (lncRNAs) in epithelial ovarian cancer (EOC) development. Research in the Lawrenson Laboratory uses RNA-sequencing technologies to catalogue the lncRNA transcriptome of ovarian cancers and their precursor tissues: specifically, ovarian surface epithelial cells and fallopian tube secretory cells for the most common subtype (high-grade serous). A current focus of the Lawrenson Lab is a specific lncRNA—UCA1—that is associated with poor outcomes in EOC. In vitro studies indicate that this long noncoding RNA induces metabolic reprogramming in ovarian cancer cells and perturbs a key pathway involved in development and cancer. Current investigations in the Lawrenson Lab are exploring the mechanisms by which UCA1 promotes ovarian cancer development and whether UCA1-regulated pathways represent molecular vulnerabilities in UCA1-driven cancers that can be targeted therapeutically.
Elucidating the Function of Risk and Somatic Variants Associated with Ovarian Cancer
Genome-wide association studies have identified a plethora of genetic variants that influence a person’s risk of developing complex traits, including cancer. The overwhelming majority of these variants lie in noncoding DNA. More recently, whole-genome sequencing studies have catalogued on average 10,000 variants per ovarian tumor, the majority of which are outside of coding exons. These analyses highlight a central role for gene regulation in cancer risk and somatic development, and so it has been necessary to develop novel approaches to the functional analysis of these polymorphisms: first, to identify the regulatory biofeature coinciding with the variant and, second, to identify and characterize the target gene or genes. The Lawrenson Lab uses in vitro models, genome editing, ChIP-seq and RNA-seq to identify and test the function of novel variants and their target genes.
Identifying Novel Therapeutic Approaches for Women's Cancers
Three-dimensional cell culture models and cell culture systems developed from biologically relevant tissues represent unique resources for profiling active pathways in disease and responses to chemotherapeutic agents or targeted therapies. The Lawrenson Laboratory has generated 3-D models of EOC precursor tissues and shown that 3-D cell culture models of ovarian cancer cell lines can recreate the histological diversity of ovarian cancers. Moreover, 3-D ovarian cancer cultures also tend to be more chemoresistant, indicating that 3-D culture systems are more stringent drug development platforms. The Lawrenson Laboratory is now using these novel 3-D model systems to test novel therapeutic strategies for the treatment of ovarian cancer.
Discovering Molecular Drivers and Clinical Biomarkers for Endometriosis
Endometriosis is characterized by endometrial glands and stroma outside of the uterine cavity, causing chronic pain, dysmenorrhea and infertility. Endometriosis is present in up to 10 percent of reproductive-aged women. True prevalence of the disease in the general population is likely grossly underestimated, as many women may be asymptomatic, and the associated symptoms are variable and not specific to this disease (e.g., pelvic pain). Consequently, a definitive diagnosis usually requires surgery.1 In addition to pain and infertility, endometriosis is associated with increased risk of ovarian cancer, particularly the clear cell and endometrioid ovarian cancer subtypes (the endometriosis-associated ovarian cancers, EnOCs).2-6
The economic burden of endometriosis is substantial,7 with the direct costs per patient in the U.S. reaching over $12,000 annually. Indirect costs are also large, primarily due to loss of work productivity as a result of pain and illness. The total financial burden of endometriosis in the U.S. is now thought to exceed $75 billion dollars annually.8 In spite of this, many basic questions about endometriosis etiology remain unanswered. For example, endometriosis is divided into four stages (I to IV) to describe the extent of the adhesions and implants observed. However, it is not clear whether the different stages represent different parts of the same disease continuum or distinct endpoints. Endometriosis can also be described according to disease site: ovarian endometriosis (endometrioma), deep infiltrating disease, and peritoneal lesions. Deep infiltrating disease is the most aggressive subtype, with cancer-like invasive behavior and frequent mutations in known cancer driver genes. Somewhat paradoxically, however, this subtype of endometriosis is not associated with increased ovarian cancer risk, whereas many studies have now shown that ovarian endometriosis is associated with increased risk.9,10
To address these crucial questions, the Lawrenson Laboratory has established the Biological and Epidemiological Markers of Endometriosis Study at Cedars-Sinai, working in close collaboration with the surgeons in the Minimally Invasive Gynecologic Surgery Center. The study is collecting tissues and blood from affected patients and has ongoing studies to understand cellular and transcriptional heterogeneity in endometriosis and identify novel circulating biomarkers.