Northwestern University PS-OC
Chicago Region Physical Science Oncology Center (CR-PSOC)
The CR-PSOC is organized around the conceptual framework that addresses the spatio-temporal organization of chromatin and information transfer in cancer. This organizing framework integrates the strengths of chemistry, genetics, and physics to address chromatin dynamics in cancer.
Through the use of shared model systems PS-OC investigators are able to integrate data from across projects to develop a new conceptual understanding of the mechanisms underlying physical rearrangement of chromatin in cancer and how that controls gene expression.
This PS-OC is composed of interrelated project areas, each focused on different aspects of chromatin structure and function. Each project integrates emerging physical science approaches and molecular and cancer cell biology tools, as well as theory and modeling methods from the physical sciences, to achieve a quantitative and predictive understanding of the of deregulation of chromatin mechanics, epigenetic regulatory pathways, gene expression, and the nuclear environment in cancer.
The PS-OC projects maintain a clear cancer focus rooted in understanding the molecular mechanism behind genetic alterations in chromatin regulators in cancer, particularly hematological malignancy.
Project 1: Ionic Modulation of Chromatin in Cancer
This project focuses on the ionic composition of nuclei in cancer and its role in modulating chromatin conformation, nuclear shape, and, ultimately, its impact on gene expression and the emergence of cancer phenotypes.
PS-OC investigators are testing the proposition that a massive ion imbalance is a significant contributor to the transformed phenotype of metastatic breast cancer, glioblastoma, and multiple myeloma cancer cells. They are using whole cells, animal models of cancer, and an array of physical methods (including vital imaging probes, Partial Wave Spectroscopy, x-ray fluorescence microscopy, nuclear nanomechanics and EDS-STEM ultrastructure studies).
The overarching goal of this project is to translate these physical science insights into the role of the intracellular ion concentrations in modulating tumor cell behavior into the development of new targets for therapeutic intervention in metastatic disease.
Project 2: Molecular Modulation of Chromatin and Nuclear Structure in Cancer
This project is elucidating the role of enhancer dysfunction in modulating the spatio-temporal organization of chromatin and information transfer in cancer.
Experiments are testing the hypothesis that enhancer dysfunction leads to an altered physical state of chromatin, including an abnormal state of 3-D looping, leading to aberrant formation of transcriptional initiating and elongating complexes, destroying the normal balance of gene expression in the cell. The sequelae of these events are ineffective hematopoiesis and clonal expansion of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) precursors.
Emerging CRISPR technology, sophisticated chromatin confirmation capture and genome wide chromatin surveys are being used to investigate the aberrant structure and function of chromatin.
Project 3: Mechanics of Nuclei, Chromosomes and Chromatin in Cancer
This project is analyzing the variation in chromatin structure – from the fiber level to chromosomes to the whole cell nucleus – using physical tools in combination with state-of-the-art cell biological approaches.
Aim 1 is based on the hypothesis, supported by an array of preliminary data, that the physical organization and mechanics of chromosomes and nuclei are altered in cancer cells. This is being tested using micromechanical studies of nuclei and chromosomes, combined fluorescence imaging of major chromosome- and nucleus-organizing proteins, and partial-wave spectroscopy measurements of nuclear disorder.
Aim 2 is testing how removal of specific chromosome-organizing proteins affects chromosome and nuclear structure.
The results from these aims, in combination with Hi-C data, are being used to develop mathematical models of metaphase chromosome and interphase nucleus organization, and in combination with gene regulation network modeling, to predict effects of drug and genetic interventions for further experiments.
Aim 3 focuses on how chromatin fibers themselves are physically altered in different cell types in single-chromatin-fiber assembly and mechanics experiments. It is a comprehensive study of how chromatin and chromosomes are remodeled in cancer cells relative to normal cells, and how this remodeling affects gene expression.
Core 1: Nanocytometry
The Nanocytometry Core supports a broad range of photonics studies deploying two novel super-high-resolution microscopy methods:
- Stochastic Optical Reconstruction Microscopy (STORM)
- Partial Wave Spectroscopy (PWS) microscopy.
PWS is a novel spectroscopic microscopy technique, which was developed by Dr. Vadim Backman’s lab that is capable of quantification of intracellular structure at subdiffractional length scales. It can image modifications of higher order chromatin structure in the pre-initiation of transcription associated with a shift in genomic homeostasis to a globally more transcriptionally active state.
STORM is an established super resolution technique that is capable of providing resolution down to sub 10-nm range for biological specimens.
The CR-PSOC depends on this core for PWS and STORM analyses of cells, nuclei and metaphase chromosomes.
Core 2: PDX Human Tumor Model
This core creates and maintains carefully delineated, in vivo human tumor models from a broad range of histologies that retain the characteristics of fresh human tumors. These patient-derived xenograft (PDX) models are passaged continuously in vivo and are never exposed to tissue culture plastic and the limitations imposed by tissue culture selection of certain tumor cell clones. The PDX tumors retain histological characteristics that are similar to the patient tumors from which they were derived. Thus, these models are thought to be closer to the clinical situation than traditional xenograft models.
Models are being made available to investigators across the PS-ON.
The core is building will build on an already established PDX repository infrastructure that currently maintains 62 models covering 10 different tumor histologies. 2-3 new models are created each week. Early passage cell lines are created in parallel from these in vivo PDX models and are being made available to PSOC investigators, as well as potentially to investigators in PS-ON.
Education and Outreach Unit
This PS-OC supports an undergraduate summer research program and events to promote the dissemination of research and collaboration. It also sponsors roundtable discussions by clinicians and talks by authors of popular books on cancer.
Thomas V. O’Halloran, Ph.D.
Dr. Thomas V. O’Halloran is the Charles and Emma Morrison Professor of Chemistry and Professor of Molecular Biosciences at Northwestern University. He is widely known for his transdisciplinary research program spanning chemical synthesis, analytical chemistry, biochemistry, molecular biology and cell biology. In his role as the Director of the Chemistry of Life Processes Institute, Dr. O’Halloran administers and leads teams of interdisciplinary biomedical researchers. This Institute brings together researchers from the fields of chemistry, biology, physics, engineering, medicine, proteomics, molecular therapeutics and biological molecular imaging. He also serves as the Associate Director for the Basic Sciences Research Division of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Professor O’Halloran received his BS and MA degrees in Chemistry from the University of Missouri, and a Ph.D. in 1985 from Columbia University in Bioinorganic Chemistry. He joined the faculty of Northwestern University in 1986 after postdoctoral training at MIT. Dr. O'Halloran is the Morrison Professor in the Department of Chemistry and in the Department of Molecular Biosciences at Northwestern. In his tenure at Northwestern University, he has supervised over 40 Ph.D. theses and more than 25 postdoctoral fellows. Dr. O'Halloran's scientific recognitions include a National Science Foundation Presidential Young Investigator Award, a National Searle Scholars Award, an Alfred P. Sloan Research Fellowship, the Camille and Henry Dreyfus Foundation Teacher-Scholar Award, the Bioinorganic Award from the Royal Society of Chemistry and the American Society of Biochemistry and Molecular Biology Schering-Plough Scientific Achievement Award. He is a Fellow of the Royal Society of Chemistry, the Japanese Society for the Promotion of Science and the American Association for the Advancement of Science and a John Simon Guggenheim Fellow. Dr. O'Halloran received a MERIT award from the National Institutes of Health.
Jonathan Licht, M.D.
Dr. Jonathan D. Licht is the Johanna Dobe Professor of Medicine at Northwestern University and has served as Director of the Division of Hematology/Oncology and Associate Director for Clinical Sciences Research of the Robert H. Lurie Comprehensive Cancer Center since the spring of 2006. Dr. Licht sees patients with hematological malignancies including leukemia, lymphoma myeloma while directing a laboratory based translational research program. Dr. Licht, a graduate of Columbia University College of Physicians and Surgeons, trained in medical oncology and molecular biology at the Dana-Farber Cancer Institute of Harvard Medical School. On the faculty of the Mount Sinai School of Medicine for 15 years, he rose to the rank of Professor of Medicine and Associate Dean for Cancer Programs before his recruitment to Northwestern in 2006. Since that time, he has built a robust basic research group within the Division of Hematology/ Oncology.
Dr. Licht' s laboratory studies aberrant gene regulation repression as a cause of hematologic malignancy, including acute promyelocytic leukemia, multiple myeloma and myeloproliferative neoplasms, and developing small molecules and peptides strategies to revert abnormal gene regulation and treat disease. Dr. Licht is currently the Principal Investigator of a Leukemia and Lymphoma Society Specialized Center of Excellence grant, studying gene regulation mechanisms in hematological malignancy. He is a member of the Board of Scientific Councilors of the National Cancer Institute, is a Senior Editor of Clinical Cancer Research and serves on the editorial board of Oncogene. He also served as a Councilor of the American Society for Clinical Investigation and is a member of the Association of American Physicians. Dr. Licht is a charter member of the NIH Cancer Molecular Pathology Study section and has served on American Cancer Society and Leukemia and Lymphoma Society review panels.