Research Areas

Characterizing the lncRNA Landscape of Ovarian Cancer

Integrating RNAseq expression data with epigenetic biofeatures to identify lncRNAs differentially expressed in ovarian cancer cells compared to normal ovarian epithelial cells.

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 a key pathway involved in development and cancer. Current investigations in our laboratory are exploring the mechanisms by which UCA1 promotes ovarian cancer development, and are asking whether UCA1-regulated pathways represent molecular vulnerabilities in UCA1-driven cancers that can be targeted using small molecular inhibitors

Elucidating the Function of Cancer Variants

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, 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 single nucleotide polymorphism (SNP), and second to identify and characterize the target gene or genes. Lawrenson's past experience in studies aiming to elucidate the role of ovarian cancer risk SNPs has led to the Lawrenson Lab's current interest in applying similar approaches to the characterization of germline variants in coding genes, or somatic variants occurring in epigenetic biofeatures. We use in vitro models, genome editing, ChIPseq and RNAseq to identify and test the function of novel variants and their target genes.

Functional characterization of HOXD9, a novel gene involved in risk of mucinous ovarian cancer. (a) Generation of overexpression models (b) characterization of the models using anchorage independent growth assays. From Kelemen, Lawrenson et al., Nat Genet. 2015 Aug;47(8):888-897.

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. We have generated three-dimensional (3-D) models of EOC precursor tissues and have 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.

Three-dimensional cultured ovarian cancer cells more closely mimic the histology of human ovarian cancer histological subtypes: (a) low-grade serous ovarian cancer, (b) high-grade serous ovarian cancer, (c) poorly differentiated ovarian cancer (d) clear cell ovarian cancer. From Lee et al. Lab Invest. 2013 May;93(5):528-542.