Our overall aim is to understand the precise ways in which cells change at the earliest time points during cancer formation. We are focused on melanoma, the most serious form of skin cancer, which takes the lives of nearly 10,000 Americans each year. We sought, and are grateful to have received support from, the Cancer Research Foundation to characterize and modify the precise set of genes that are turned on and off at the earliest time point of melanoma formation. In order to capture these early events, we use a model of melanoma in the zebrafish which is highly reflective of the human disease in its behavior and allows us to uniquely see the first cell of cancer when it develops. We can grow and analyze many more tumors at earlier time points with this model than would ever be possible using human samples, and our results will still directly applicable to the human condition. In particular, we aim to understand and modulate the precise physical arrangement and modifications of the DNA in the nucleus, which provides the code for these genes that control the cells’ behavior; this analysis falls into the rapidly expanding area of “epigenetics” and holds great promise for identifying new and powerful methods of disease treatment and detection.

I am happy to report that we have made great progress in the past year, and expect to make substantial strides in the final year of our funding from the CRF. We have collected a large set of melanoma tumors and performed analysis on their gene expression and associated DNA arrangement/epigenetic state. This dataset is the largest to date from the zebrafish melanoma model, and may well be the largest available from any such defined set of melanoma samples. From this data, we are identifying numerous, on the order of hundreds, of regions of the nuclear DNA that are important for controlling the genes which turn on and off at the earliest points in melanoma formation. This foundational study will provide important information for many years to come as individual regions are studied in detail. In the near term, we are continuing to focus our efforts on the most prominent and likely most critical regulatory domains, as described in our original proposal, and have begun this in-depth analysis. This analysis will bring us substantially closer to finding the signals or environmental changes that ultimately alter gene expression and lead to melanoma onset.

Most recently, in monitoring our zebrafish model for melanoma formation and for collecting appropriate specimens, we noted an amazing dependence of tumor onset rate with feeding amount in the zebrafish. In short, the more fish are fed, the faster tumors form, and this observation is reported in our group’s publication in Biology Open this month. This robust effect speaks directly to our main question of how melanoma onset is regulated and ties in with other fields of metabolism, which likely play a key role in regulating these earliest gene expression changes that we aim to understand.

For my lab as a whole, the CRF funding has been extremely helpful in growing the group. In addition to our full time and part time technicians, I have recently welcomed a third graduate student to our group and have had four other students complete rotation projects over the past half year, with the goal that additional students will join. I am very excited to be presenting our most recent findings from our ATAC/RNA-seq analyses at a plenary session as an invited speaker at the AACR special conference on “Targeting DNA Methylation and Chromatin for Cancer Therapy” in March. Many leaders in the field of epigenetics and cancer will be present, and I anticipate receiving helpful feedback on our project.

Finally, as this current project continues to develop, my ongoing efforts to receive additional funding have been greatly supported by this CRF award. In addition to being selected as a candidate from Washington University for other foundation awards such as the Pew-Stewart and Damon Runyon awards, I plan to submit an R01 in 2018 as well as apply to melanoma-focused foundations (i.e. MRF, MRA, Harry Lloyd Foundation), which will be an essential component of my research groups’ continued progress.

Thank you again for this generous and essential support. I look forward to reporting additional positive news in the coming year.