Center for Cancer Systems Therapeutics (CaST)
Overview
-
Center Title
- Columbia University Center for Cancer Systems Therapeutics
-
Center Website
- http://systemsbiology.columbia.edu/cast
Center Summary
The Columbia University Center for Cancer Systems Therapeutics (CaST) is developing a new conceptual framework capable of accounting for the extreme biological heterogeneity seen in cancer. Instead of focusing on the highly diverse, patient-specific spectrum of mutations that can initiate cancer, CaST is concentrating on the regulatory machinery found within cancer cells that is responsible for tumor homeostasis and tumor canalization. Just as regulatory networks have been shown to enable cells to differentiate during development and maintain stable phenotypes, CaST is testing the hypothesis that similar regulatory principles can be used to understand how cancer cells survive and propagate as tumors grow and respond to treatment. Understanding the regulatory logic behind tumor homeostasis and canalization over the time course of disease is critical for addressing several key challenges facing precision medicine; namely, how malignant tumors evade treatment, induce disease progression, and develop drug resistance. We are studying this machinery across multiple levels of granularity — including interactions between tumors and their microenvironment as well as single-cell heterogeneity and plasticity — representing the full, systems-wide complexity of the tumor phenotype.
Our approach is based on the proposition, validated repeatedly in previous research at Columbia, that tumor homeostasis is controlled by a small number of proteins and other gene products called master regulators (MRs), which work in concert within tightly autoregulated modules called tumor checkpoints to maintain cancer-related phenotypes. Similar to a traffic checkpoint, the aberrant signals that contribute to the implementation and maintenance of tumor cell state must converge on these modules, where they are integrated and translated into downstream transcriptional programs that generate the tumor signature. As our past research has shown, such tumor checkpoints are likely much more limited in number than the possible number of cancer-initiating mutations, and therefore constitute a unique kind of oncogene-independent “Achilles heel” of cancer, offering a distinct category of potential therapeutic targets. We aim to develop methods for systematically identifying master regulators of tumor homeostasis and tumor state transitions, and connect them to drugs capable of modulating them.
Investigators
Principal Investigators
Andrea Califano, Ph.D.
Andrea Califano, Ph.D. is the Clyde and Helen Wu Professor of Chemical Systems Biology at Columbia University Medical Center. He is the Founding Chair of the Columbia University Department of Systems Biology, Director of the JP Sulzberger Columbia Genome Center, and Associate Director for Bioinformatics of the Herbert Irving Comprehensive Cancer Center. He is also the founder of Darwin Health. The Califano Lab uses a combination of computational and experimental methodologies to reconstruct the regulatory logic of human cells in a genome-wide fashion. He has shown that analysis of this logic can identify master regulator proteins responsible for human disease, including cancer and neurodegenerative syndromes, as well as for normal tissue development. In addition, his lab has developed methods for discovering compounds and compound combinations that can inactivate these proteins, thus providing valuable therapeutic strategies. These findings have been translated into several clinical studies, including an innovative set of N-of-1 clinical trials in which disease master regulators are identified and pharmacologically targeted on an individual patient basis, using a systems biology approach to precision medicine.
Barry Honig, Ph.D.
Barry Honig, Ph.D. is professor of Biochemistry and Molecular Biophysics and is director of the Center for Computational Biology and Bioinformatics (C2B2). He is a member of the National Academy of Sciences and the American Academy of Arts and Sciences, and is a Howard Hughes Medical Institute (HHMI) Investigator. Dr. Honig has developed methods that combine information about protein sequence with biophysical analysis to reveal how biological specificity is encoded on protein structures. His laboratory also uses methods from biophysics and bioinformatics to study the structure and function of proteins, nucleic acids, and membranes. His work includes fundamental theoretical research, the development of software tools, and applications to problems of biological importance.
Participating Investigators
Cory Abate-Shen, Ph.D.
Cory Abate-Shen, Ph.D. is the Michael and Stella Chernow Professor of Urologic Sciences, director of research in the Columbia University Department of Urology, and an associate director of the Herbert Irving Comprehensive Cancer Center and leader of its Prostate Program. In her research she investigates the molecular mechanisms of homeobox genes in development and cancer. Her laboratory has provided groundbreaking insights on the molecular bases of how homeoproteins achieve target gene recognition in vivo. She has also developed mouse models of prostate cancer that have been widely used to investigate the molecular bases of prostate tumorigenesis and as preclinical models for intervention and therapy.
Dimitris Anastassiou, Ph.D.
Dimitris Anastassiou, Ph.D. is Charles Batchelor Professor and director of the Genomic Information Systems Laboratory at the
Department of Electrical Engineering, and a member of the Department of Systems Biology, Center for Computational Biology and Bioinformatics, and the Center for Cancer Systems Therapeutics (CaST). His current research is focused on the discovery and elucidation of “pan-cancer” biomolecular mechanisms shared by multiple cancer types, as well as potential diagnostic, prognostic, and therapeutic applications associated with these mechanisms.
Filemon Dela Cruz, M.D.
Filemon Dela Cruz, M.D. is an assistant professor of pediatrics at Memorial Sloan Kettering Cancer Center. His current work focuses on the development and application of mouse models for the study of the development of solid tumors, with a particular focus on sarcomas.
Charles Karan, Ph.D.
Charles Karan, Ph.D. is the scientific director for the High-Throughput Screening Facility at the JP Sulzberger Columbia Genome Center. In this role, he assists researchers at Columbia and from other institutions to develop and implement high-throughput screening protocols tailored to the goals of individual research projects. He also manages all operations of the HTS facility.
Andrew Kung, M.D. is a physician-scientist and Chair of the Department of Pediatrics at Memorial Sloan Kettering. He oversees the clinical, research, and educational missions of the department. As a physician, he specializes in caring for patients using cancer genomics, precision medicine, and stem cell transplantation. In his research, he focuses on identifying the causes of pediatric cancers and developing new treatments to benefit children and teens with cancer.
Diana Murray, Ph.D.
Diana Murray, Ph.D. is a Research Scientist and the Program Director of Research and Outreach in the Department of Systems Biology. Her research focuses on integrating structure-based protein-protein interaction networks with gene regulatory networks to provide molecular-level descriptions for mechanisms underlying normal and aberrant cellular signaling. Building on a computational framework for examining phosphoinositide signaling, she will participate in CaST’s research by incorporating proteomic and genomic information on protein-lipid interactions into structure-informed network models. In addition, Dr. Murray is leading the CaST Outreach Corer.
Kenneth Olive, Ph.D.
Kenneth Olive, Ph.D. is Assistant Professor of Medicine and Pathology at the Columbia University College of Physicians & Surgeons. His laboratory performs preclinical therapeutics trials using advanced genetically engineered mouse models, with a particular emphasis on pancreatic cancer. The lab uses advanced small animal imaging technologies to track tumor response to treatment, as well as pharmacokinetic and pharmacodynamics analyses, functional imaging, microscopy, and biochemistry and molecular biology techniques to assess drug mechanisms and understand relevant signaling pathways.
Itsik Pe’er, Ph.D.
Itsik Pe’er, Ph.D. is an associate professor in the Department of Computer Science. His laboratory develops and applies computational methods for the analysis of high-throughput data in germline human genetics. Specifically, he has a strong interest in isolated populations such as Pacific Islanders and Ashkenazi Jews. Using high-throughput sequencing methods, Pe’er has focused on characterizing genetic variation that is unique to isolated populations, including the effects of such variation on phenotype.
Raul Rabadan, Ph.D.
Raul Rabadan, Ph.D. is an Associate Professor with joint appointments in the Departments of Systems Biology and Biomedical Informatics. He is also a member of the Scientific Advisory Board of the JP Sulzberger Columbia Genome Center, and codirector of the Center for Topology of Cancer Evolution and Heterogeneity, a center in the NCI’s Physical Sciences–Oncology Network. At Columbia University, Dr. Rabadan leads an interdisciplinary lab with researchers from the fields of mathematics, physics, computer science, engineering, and medicine who share the common goal of solving pressing biomedical problems through quantitative computational models. His work is focused on developing tools to analyze genomic data, and extracting relevant information to understand the molecular biology, population genetics, evolution, and epidemiology of cancer.
Nicholas Tatonetti, Ph.D.
Nicholas Tatonetti, Ph.D. is Herbert Irving Assistant Professor of Biomedical Informatics at Columbia University with interdisciplinary appointments in the Department of Systems Biology and the Department of Medicine. Dr. Tatonetti researches the use of observational clinical data and high-throughput molecular data to identify and explain the pharmacological effects of drugs and drug combinations. He also develops large-scale statistical and data mining techniques to address issues of bias and confounding in large observational data sets.
Dennis Vitkup, Ph.D.
Dennis Vitkup, Ph.D. is an associate professor in the Departments of Systems Biology and Biomedical Informatics. His laboratory develops and applies novel probabilistic techniques to analyze cellular networks, connecting network structure to function to phenotypes, including experimentally verifiable predictions. Research in the Vitkup Lab focuses on three main topics: 1) the global probabilistic reconstruction and analysis of metabolic networks based on completely sequenced genomes; 2) the development of methods to identify new human disease genes and genetic disease modules using probabilistic functional networks; and 3) the development of methods to combine mechanistic and probabilistic approaches for the dynamic simulation of biological pathways.
Harris Wang, Ph.D.
Harris Wang, Ph.D. is an Assistant Professor in the Department of Systems Biology and Department of Pathology and Cell Biology at Columbia University Medical Center. Using approaches from genome engineering, DNA synthesis, and next-generation sequencing, he is currently studying how genomes in microbial populations form, maintain themselves, and change over time, both within and across microbial communities. His goal is to use synthetic biology approaches to engineer ecologies of microbial populations, such as those found in the gut and elsewhere in the human body, in ways that could improve human health.
Core Director
Peter Sims, Ph.D.
Peter Sims, Ph.D. is an assistant professor in the Departments of Systems Biology, and Biochemistry and Molecular Biophysics at Columbia University, and associate director of the JP Sulzberger Columbia Genome Center. Trained in physical chemistry, he is interested in developing new tools for single-cell analysis, applying cutting-edge microscopy, next-generation sequencing, and microfabrication to enable unbiased, system-wide measurements of biological samples. He and his colleagues focus on single-cell transcriptomics and sequencing technology along with novel approaches to proteomics, where current tools lag far behind those available for nucleic acid analysis. He is leading the CaST Molecular Profiling Core.
Project Manager
Aris Floratos, Ph.D.
Aris Floratos, Ph.D. is an assistant professor in the Departments of Systems Biology and Biomedical Informatics and executive research director at the Center for Computational Biology and Bioinformatics. He has led the development of GeWorkbench, a free, open source bioinformatics application that gathers the Department’s software and databases into one integrated software platform.
Projects
Project 1: Elucidating the regulatory logic that is responsible for maintaining cancer cell state, independent of specific initiating events and endogenous/exogenous perturbations
In project 1, CaST is attempting to move beyond current approaches for elucidating tumor checkpoints and master regulators, which are largely static and not designed to predict how tumors respond to pharmacological and genomic perturbations over time. Thus, we are developing novel methodologies to mechanistically uncover the regulatory machinery that maintains cancer cell state and governs cell state transition. We are also working to define the role of regulatory networks in implementing distinct tumor phenotypes, from metastatic progression, to immunoevasion, to drug resistance. This effort will leverage and integrate time-course data from gene expression and computationally inferred protein activity profiles, generated by small molecules and RNAi/CRISPR perturbations.
Project 2: Elucidating time-dependent mechanisms of genetic and epigenetic reprogramming of individual cancer cells underlying cancer-state transitions to drug resistance and progression
We are investigating cell state plasticity and tumor/microenvironment heterogeneity, which represent formidable obstacles to successful treatment of human malignancies. This interest is driven by a growing awareness that tumors can harbor distinct niches that include genetically distinct subclones (which have identical or distinct tumor checkpoints), as well as isogenic niches (which present with orthogonal checkpoints). Our goal is to compile a comprehensive inventory of tumor dependencies among such heterogeneous niches that can be targeted pharmacologically, We are studying these mechanisms by developing new methods to identify distinct tumor compartments and heterogeneity at the single-cell level.
Project 3: Developing novel methodologies for the systematic prioritization of compounds and compound combinations capable of abrogating tumorigenesis in vivo
We are developing and validating computational methods for the prioritization of master regulator-targeting drugs and drug combinations to either implement or prevent specific tumor state transitions. This includes inducing irreversible commitment to cell death, preventing progression to a malignant tumor stage, and rescuing drug sensitivity. In addition, we are attempting to address a broad range of questions related to the heterogeneity of tumor response, including mechanisms that allow tumor cells to compensate for MR-targeted therapy. We propose that addressing tumor plasticity and potential escape routes implemented by tumor state reprograming is going to be critically relevant for the chronic management of cancer in patients.
Cores
Molecular Profiling Core
A technical requirement for achieving CaST’s scientific goals is access to cost-effective, cutting-edge molecular profiling, high-throughput screening, and single-cell analysis tools utilizing robotics and microfluidics. The Molecular Profiling Core (MPC) provides three key capabilities: 1) PLATESeq: a novel platform for integrating high-throughput screening with genome-wide expression profiling; 2) microfluidics: a highly multiplexed, microfluidic implementation of PLATESeq that produces expression profiles across hundreds of single cells in parallel; and 3) single-cell whole genome sequencing: a pipeline that combines microscopy-based single cell isolation with whole genome amplification for single-cell whole genome sequencing.
Outreach Core
In addition to pursuing research, CaST conducts outreach to disseminate the software and methods developed by the Center, foster discussion on related issues within the larger scientific community, support community-based research efforts, and mentor young scientists. These activities include 1) supporting the DREAM challenges; 2) a cross-training program to help investigators gain experience with complementary methods and perspectives; 3) a “CaST Scholars” program that enables undergraduate students to participate in our research; and 4) organizing scientific meetings on related topics in cooperation with the New York Academy of Sciences Systems Biology Discussion Group.