Research Professor of Cancer Genetics and Molecular Biology
Cold Spring Harbor Laboratory
Cold Spring Harbor, New York
Project 1: Co-Investigator: Michael H. Wigler, PhD, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
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.
Project 2: Co-Investigator: Peter Kuhn, PhD, The Scripps Research Institute, La Jolla, CA
Patients with breast cancer would benefit significantly from precise characterization of their disease at multiple time points throughout the course of the disease. This can be accomplished by utilizing a simple blood draw as a fluid biopsy. This fluid biopsy can be used to identify rare circulating tumor cells (CTCs) and also circulating genomic fragments that together provide the opportunity for a complete description of the disease. This project, led by Drs. Kuhn and Hicks, develops and applies the next generation technology to provide this data to the physician to aid in treatment decisions.
Project 1: 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.
Project 2: Patients with breast cancer would benefit significantly from precise characterization of their disease at multiple time points throughout the course of the disease. This can be accomplished by utilizing a simple blood draw as a fluid biopsy. This fluid biopsy can be used to identify rare circulating tumor cells and also circulating genomic fragments that together provide the opportunity for a complete description of the disease. This research project, which is being carried out jointly by Dr. James Hicks at Cold Spring Harbor Laboratory and Dr. Peter Kuhn at The Scripps Research Institute, is designed to develop and validate a novel form of fluid biopsy combining the enumeration and genomic analysis of circulating tumor cell with a detailed genetic analysis of free DNA circulating in the blood plasma from the same patient. The goal is to determine which assay (or a high content combination) yields the most relevant information for designing effective treatment for each patient. In this grant period they have validated the methodology in pilot experiments and are poised to compare the two assay types in samples from actual patients, and determine how to best provide this complex data to the physician to aid in breast cancer treatment decisions.
Dr. James Hicks received his doctorate in Molecular Biology and Genetics from the University of Oregon, after which he completed a post-doctoral fellowship in Genetics at Cornell University. He first joined the Cold Spring Harbor Laboratory as a Senior Staff Investigator before pursuing opportunities in industry.
Since returning to Cold Spring Harbor Lab in 2003, Dr. Hicks has been engaged full-time in the development and application of tools for high resolution genomic and epigenomic analysis. Taking genomic and epigenomic resolution to the single cell level is ultimately necessary for a deep understanding of their roles in cancer and embryonic development. Dr. Hicks’s group is currently applying these tools to retrospective clinical trials with the goal of understanding the initiation and progression of cancer and of finding biomarkers for cancer and neurobehavioral disease.