Cold Spring Harbor Laboratory
Cold Spring Harbor, New York
Since their development of single cell genomics in 2011, which was supported in large part by BCRF, cancer research in the Wigler and Hicks laboratories at Cold Spring Harbor Laboratory has focused on the genetic dissection of breast tumors at their most granular level, the single cells that make up the complex landscape of cancer. Through this group’s work and others’, it has become clear that some breast cancers are made up of heterogeneous mixtures of cells, thus obfuscating the results of most molecular assays for classifying tumors. Drs. Wigler and Hicks have long maintained a goal of identifying genetic markers that could help direct treatment of cancers and relieve suffering by making treatment more effective for the individual patient. They can do that best by developing tools to understand the genetic makeup of breast tumors at the cellular level and the development of assays that could resolve genetic complexity of individual cancer cells. Through support from BCRF, Drs. Wigler and Hicks are using these new tools to examine cancers at an unprecedented level of resolution and to employ these tools in clinical studies on real patients. A major focus of their single cell work is on the mechanisms underlying metastasis, the real cause of mortality in breast cancer. Their ability to identify and follow rare cells through a combination of single cell profiling and targeted high-depth DNA sequencing will allow them to isolate rare cancer cells from the bloodstream and to use those cells to track the progress of therapy, ultimately yielding genetic markers that will match the right treatment with the right patient. This year’s project focuses on understanding how these circulating cells seed metastatic locations, determining how they evolve once at a metastatic site, and whether they continue to move around the body.
Utilizing Dr. Michael Wigler and Dr. James Hicks’ single cell sequencing technology opens up immense new clinical possibilities, such as improvements in the assessment of prognosis and treatment and in the efficacy of the analysis of needle biopsies, evaluation of the risks inherent in carcinoma in situ, and early detection of breast cancer and breast cancer recurrence. Drs. Wigler and Hicks have focused on optimizing bench and data processing protocols in order to standardize their approach and make it exportable to other laboratories as well as to begin answering important questions in breast cancer biology, such as how tumor cells move in the body and what makes a tumor metastatic. In this grant period they have made progress on two of their three aims. First, they have refined and tested a new method for combining single cell DNA amplification and preparation for sequencing that will speed up single cell genomic analysis and reduce costs by half. Second, they are using DNA mutations as markers to track the migration of cells between tumor sites in single patients. This project is now at the preliminary stage of analyzing the resultant DNA sequences. The final project, examining the genomic structure of large, untreated tumors that do not metastasize has just received approval from the Institutional Review Board to proceed, and will be pursued in the following grant period.
Dr. Wigler grew up in Garden City, on Long Island, New York. He attended Princeton University as an undergraduate, and Columbia University for graduate studies. After graduate school, he commenced his independent scientific studies at Cold Spring Harbor Laboratory, where he continues his work to this day. He is a recipient of numerous awards and honors, and is a member of the National Academy of Science, the American Academy of Arts and Sciences.
While Dr. Wigler was a graduate student, he developed effective and flexible methods for engineering animal cells, a method that is the basis for the production of medicinally useful proteins even today. After moving to Cold Spring Harbor Laboratory, Dr. Wigler continued his studies of gene transfer, exploring the integration of foreign DNA and the stability of gene expression in transfected cells, demonstrating the inheritance of DNA methylation patterns, and isolating the first mammalian genes, such as the ras oncogenes, using DNA transfer and genetic selection. His laboratory was among the group that first showed the involvement of members of the ras gene family in human cancer. Subsequently, Dr. Wigler used yeast as model genetic systems for the study of signal transduction pathways and oncogenes, culminating in the elucidation of the ras oncogene pathway in yeasts and humans.
In the early nineties, Dr. Wigler and collaborators developed the first method for encoded combinatorial chemical synthesis, a method that is used today for drug discovery, and developed a powerful method for DNA difference analysis called RDA. This method has led to the identification of many new oncogenes, tumor suppressors and pathogens.
Dr. Wigler continues to work in the area of cancer and human genetic disease, and most recently has developed microarray based hybridization methods for comparing the genomes of diseased and healthy cells.