Research in my laboratory is focused on ovarian, prostate, and occassionally other disease sites. We apply our discoveries of cancer dependencies in cell signaling, proliferative control, chromatin organization, and genome integrity to new therapeutic approaches for these types of cancer.

Rb1 mutant mice

Telomere staining of chromosomes

ChIP-seq data.

Alazarin Red stain of DREAM mutant mouse skeleton.

Numerous proteins function to organize mammalian chromatin and compact it into mitotic chromosomes during mitosis.  Errors in organizing chromatin structure inevitably lead to genome instability through DNA breaks, abnormal DNA replication, and errors in mitosis.  While this contributes to cancer pathogenesis in some contexts, it is also a potential target for cancer treatment as many chemotherapeutics exacerbate genome instability to cause cell death.  In addition, loss of  heterochromatin can misexpress silenced RNA sequences that in turn stimulate an immune response and potentially contribute to mechanisms that clear pre-malignant cells.  Our work in this area is focused mainly on Condensin II and EZH2, two chromatin structure regulators that we originally developed an interest in because they are recruited to DNA by the RB-tumor suppessor through a cell cycle independent interaction with E2F1.  Projects in this area of the lab seek to understand the fundamental organization mechanisms of heterochromatin and how they are altered in cancer, or by small molecule inhibitors.  Ultimately, the relevance of these chromatin organizing mechanisms are investigated using gene-targeted mouse models that are deficient for heterochromatin assembly, Condensin II components, or RNA pattern recognition receptors.  We expect this work will point to new vulnerabilities in cancer and better describe the effects of chromatin altering therapeutics that are currently in clinical trials or just beginning in clinical use.       

Cancer is most often characterized by inappropriate cell proliferation.  Work in this area of my lab's research is focused on circumstances where cancer cells ironically stop growing.  The ability of cancer cells to halt proliferation is critical for their ability to survive under stressful conditions where oxygen and nutrients are limiting.  In addition, prolonged cell cycle arrest allows cancer cells to escape the toxic effects of most chemotherapeutic agents that take advantage of the vulnerabilities of rapidly dividing cells.  These 'dormant' cancer cells are a significant source of disease relapse for cancer survivors, underscoring the importance of understanding how cancer cells can escape from a rapidly proliferating state and how they survive.  We are using systematic approaches to investigate which genes are needed for cancer cells to enter and survive in dormancy.  For example, we developed a new CRISPR screen workflow called 'GO-CRISPR' to maximize discovery of gene dependencies in dormancy.  In addition, we are studying the normal physiological roles for these survival mechanisms in gene targeted mice to understand their normal role in mammalian physiology and rationalize their prospects for targeting in cancer therapeutics.  One contributor to cell dormancy is the Netrin signaling pathway that supports survival specifically in dormant conditions and contributes little to the progressive disease.  Understanding and exploiting the vulnerabilities of dormant cancer cells will be key to extending the lives of breast and ovarian cancer survivors.

Heterochromatin regulation and detection of its misregulation by the immune system.

Survival mechanisms in cancer cell dormancy.

We use a range of methods from in vitro biochemical experiments and cell culture, to gene targeted mouse models of disease.  We also use the latest CRISPR based methods and next generation sequencing to ensure our experiments are systematic and comprehensive.  Current projects can be grouped into the following two general categories.