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List of Research Projects
ICBP Summer 2011 Cancer Research Fellowships/Internships
Project Descriptions (listed by training sites of the fellowships/internships)
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Broad Institute/Dana-Farber Cancer Institute
Boston, MA
Website: http://www.broadinstitute.org/science/programs/cancer/icbp/broad-institute-icbp
Principal Investigator: Todd R. Golub, M.D.
Levi Garraway, Ph.D.
Mentor: Cory Johannesson, Ph.D.
Duration of Program: June 6 through August 5, 2011
Project description: The Broad Center for Cancer Systems Biology has the overall goal of developing computational models that predict tumor vulnerabilities based on the molecular characteristics of the tumor. The ultimate goal of these efforts is to identify tumor dependencies that can be targeted therapeutically. The summer training program at the Broad Center for Cancer Systems Biology will provide an opportunity for a student to learn how to use a combination of molecular biology experimental techniques, including gain of function (gene expression) and loss of function (gene depletion) approaches. Students will perform laboratory experiments using human cancer cell lines with RNA interference and over-expression tools to test hypotheses emerging from computational analyses of tumor dependencies.
Requirements: Strong interpersonal, communication, organizational skills and attention to detail are required, including the ability to handle a variety of tasks in a fast-paced environment. Prior experience working in a molecular biology laboratory is recommended but not required.
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Columbia University
New York, NY
Websites: http://magnet.c2b2.columbia.edu/
Principal Investigator: Andrea Califano, Ph.D.
Co-Principal Investigator: Cory Abate-Shen, Ph.D.
Mentor: Alvaro Aytes, Ph.D.
Duration of Program: June 6 through August 5, 2011
Title: Assembly of a prostate cancer genome-wide molecular interactome for the identification of the key regulatory genes of malignant transformation and new targets for therapeutic intervention
Project description: A major issue in the translation of findings from mouse models to clinical practice is the lack of appropriate tools to identify causal mechanisms of oncogenesis, tumor progression, and drug activity. This project is based the belief that analyses of genetically engineered mouse models can advance the diagnosis and treatment of human cancer through the identification of new biomarkers of disease progression and outcome, and the discovery of new targets for therapeutic intervention. The student will participate in the assembly of a whole genome prostate cancer interactome, which represent the regulatory molecular interaction network of prostate cancer. This will include the generation of gene expression signatures for specific stages of the disease and the identification of the candidate master regulators of cancer progression by computational biology methods. Gain and loss of function experiments will be carried out to functionally validate the candidate genes. Finally genes will be validated for the relevance for human disease interrogating tissue microarrays by means of immunofluorescence or immunohistochemistry and applying systems pathology approaches.
Primary field of study: The student may be involved in any or all aspects of this project, depending on background, including: mouse colony managing, molecular biology techniques, cell culture, fluorescence activated cell sorting, immunohistochemistry and immunofluorescence and western blot.
Requirements: Useful experience would include: PCR and qPCR; cell culture; histology and immunohistochemistry.
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Georgetown University
Washington, D.C. (Georgetown area)
Website: http://lombardi.georgetown.edu/breastcancer/ccsb/
Principal Investigator: Robert Clarke, Ph.D.
Mentor: Louis Weiner, M.D.
Duration of Program: June 6 through August 5, 2011
Title: Functional genomics of anti-estrogen resistance
Project description: Breast cancer is frequently characterized by drug resistance, which is the major cause of disease progression and death from this disease. Many human breast cancers are initially dependent upon estrogen-related signals for proliferation and survival, and are thus sensitive to a wide range of hormonal antagonists. However, these cancers eventually develop resistance to these agents, and ultimately develop resistance to common chemotherapy agents as well. We are conducting synthetic lethal screens in hormone-refractory breast cancer cells to identify the molecular determinants of resistance to hormone antagonists and chemotherapy agents. We have previously identified genes within the estrogen receptor (ER) network that confer some drug resistance in a series of studies that have employed an small inhibitory RNA (siRNA) library targeting a 631-gene ER network. We now plan to extend these studies by determining the influences of genes related to apoptosis, alone and in combination with genes related to the ER network, on resistance to hormonal antagonists and chemotherapy agents, respectively. Students will learn to conduct the synthetic lethal screens, which will provide important insights into new approaches to circumventing drug resistance in breast cancer.
Primary Field of Study: Molecular biology
Requirements: Some familiarity with cell culture and a basic understanding of biochemistry and/or molecular biology
Key words: Functional genomics, breast cancer, molecular biology, synthetic lethal screens
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E. O. Lawrence Berkeley National Laboratory (LBNL)
Berkeley, CA
Website: http://icbp.lbl.gov/index.htm
Principal Investigator: Joe Gray, Ph.D.
Mentor: Obi Griffith, Ph.D.
Duration of Program: June 6 through August 5, 2011
Title: Development of molecular predictors for outcome and response to therapy in breast cancer
Project description: Overall mortality in breast cancer remains high. Studies have shown that breast cancers are molecularly heterogeneous and that molecular features can be used to define breast cancer subtypes with poor prognosis or predict which cancers will respond to specific therapies. A large number of gene-expression studies of breast cancers have been deposited in public databases, providing a rich resource for meta-analysis. We have
performed such a meta-analysis for estrogen receptor positive, lymph node negative breast cancers and developed an accurate predictor of disease relapse. The methods are very well defined and the summer student will simply expand the approach to additional clinical disease subtypes. The result of the project will be one or more datasets of carefully curated clinical and genomic data for use in single-gene studies and multi-gene predictors. The ultimate goal is development of diagnostic/prognostic assays for commercial and clinical use in guiding breast cancer therapeutic decision making. Research tasks will be exclusively biocomputational and will include data collection and curation from the literature, correlation analysis, normalization, clustering, variance filtering, meta-analysis, classification, and survival analysis. Co-authorship on multiple publications is likely.
Requirements: Applicants should have a background in computation, bioinformatics, or statistics, and be interested in applying this to cancer systems biology. Familiarity with the R statistical programming language is highly preferred. Knowledge of molecular biology/cancer, such as introductory courses, is desired.
Keywords: Breast cancer sub-types, biocomputational, meta-analysis, R statistical programming language
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Massachusetts Institute of Technology
Cambridge, MA
Websites: http://web.mit.edu/icbp/
Principal Investigator: Douglas Lauffenburger, Ph.D.
Co-Principal Investigator: Forest White, Ph.D.
Mentor: Amanda Rosario
Duration of Program: June 6 through August 5, 2011
Title: Lysine acetylation in cancer metabolism
Project Description: Although originally hypothesized by Otto Warburg back in the 1950s, the significance of cancer as a metabolic disease has been revisited in recent years. Warburg observed that tumors have elevated glucose uptake and noted that unlike normal differentiated cells which rely on mitochondrial oxidative phosphorylation for energy, tumor cells use anaerobic glycolysis, despite presence of oxygen. Rather than maximizing ATP production, the metabolism of cancer cells is altered to meet the large requirement of nucleotides, amino acids, and lipids needed to support cell growth and proliferation. The Warburg effect appears to satisfy the classical six hallmarks of cancer, and has been hypothesized to lead to mitochondrial dysfunction, thereby leading to genetic instability and potentially oncogenesis.
Lysine acetylation is frequently associated with histone modification and chromatin remodeling, however this protein modification is beginning to be appreciated as a regulator of other proteins. Several proteins known to be involved in cancer, such as p53, NFKB, and STAT3, have been shown to be reversible acetylated on lysine residues. Similar to techniques used in our laboratory to study protein tyrosine phosphorylation, immunoprecipitation of lysine acetylated peptides via anti-acetyl lysine antibodies followed by mass spectrometry analysis have enabled the identification of thousands of lysine acetylation sites, greatly expanding the acetylome beyond epigenetic modification. More recently, another proteomic study discovered that most metabolic enzymes are reversibly lysine acetylated, revealing the potential for these enzymes to be regulated by this posttranslational modification. While these proteins have been reported to be acetylated, how lysine acetylation affects many of these proteins is unknown.
This summer project will examine the molecular level effects of histone deactylase inhibitors (HDACi) on lysine acetylation sites and overall metabolic state of cells that are either undergoing oxidative phosphorylation or anaerobic glycolysis. It has been postulated for several years that the principal anti-cancer effects of HDACi might be non-epigenetic. Given the importance of altered metabolism to cancer cell proliferation, and the role of lysine acetylation in regulating cellular metabolism, it appears that the principal anti-cancer effect of HDACi may be due to altered acetylation of cellular metabolic enzymes. Here we will test this hypothesis by treating cells that are either undergoing oxidative phosphorylation or anaerobic glycolysis with multiple doses of HDAC inhibitors then quantify the effects on lysine acetylation at various time points. Altered acetylation patterns will be correlated with changes in metabolic state through quantification of NADH/NADPH ratios and ATP levels, and to changes in cell proliferation, migration, and invasion rates. Computational analysis of phenotypic and proteomic data sets will help identify the key regulatory nodes governing response to HDACi treatment, potentially enabling development of more specific next-generation therapeutics targeting the most important regulatory nodes.
Primary fields of study: Cancer biology, lysine acetylation, cellular metabolism
Requirements: Knowledge of cancer, cellular metabolism, and molecular biology is desired. Previous research experience is not a prerequisite, although previous experience with cell culture is helpful.
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Memorial Sloan-Kettering Cancer Center
New York City, NY
Website: http://www.mskcc.org/mskcc/html/11655.cfm
Principal Investigator: Chris Sander, Ph.D.
Mentor: Joao Xavier, Ph.D.
Duration of Program: June 6 through August 5, 2011
Title: Cell based computer modeling of tumor-microenvironment interactions
Project Description: Our lab develops computer models to predict cancer dynamics by simulating the behavior of individual cells and the interactions among them. The summer intern will work on extending our simulation framework to include cell-cell communication between cancer and stromal cells (i.e., cells in host microenvironment). This presents challenges in the mathematical modeling of the biophysical processes involved as well as in the computational implementation of those models using fast numerical solvers.
Requirements: The ideal candidate has a solid background in quantitative sciences (applied mathematics, engineering or biophysics) and experience in programming. Matlab is required; knowledge of Java and object-oriented programming is not required but is a plus. The internship is entirely computational - no bench experience is required.
Key Words: Biophysical modeling, differential equations, agent-based simulation, Matlab, Java
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Methodist Hospital Research Institute
Houston, TX
Website: http://www.methodisthealth.com/tmhri.cfm?id=39163
Principal Investigator: Stephen Wong, Ph.D.
Mentor: Xiaofeng Xia, Ph.D.
Duration of Program: June 6 through August 5, 2011
Title: Spatial localization of cancer stem cells and hypoxia in a solid tumor
Project description: The Methodist Hospital Research Institute’s Integrative Cancer Biology Program (ICBP) focuses on developing new biotechniques to identify, localize, purify and characterize cancer stem cells and developing mathematical tools to model them. One of the specific projects is to study how oxygen depletion (hypoxia) may affect the function of cancer stem cells. The proposed summer project will focus on studying the localization of cancer stem cells and hypoxia within a solid tumor, primarily using immunocytochemistry and confocal microscopy methods. The goal is to reconstruct the three dimensional (3D) distribution of cancer stem cells and hypoxia and analyze the physiologic relationship between them.
Primary field of study: Cell biology, wet lab experience
Requirements: Useful experience would include: immunocytochemistry, confocal microscopy, image processing tools
Key words: Cancer stem cells, hypoxia, confocal microscope, 3D image reconstruction
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The Ohio State University
Columbus, OH
Websites: http://icbp.med.ohio-state.edu/
http://mbi.osu.edu/
http://bioinformatics.med.ohio-state.edu/
Principal Investigator: Tim Huang, Ph.D.
Mentor: Ben Rodriguez, Ph.D.
Duration of Program: June 6 through August 5, 2011
Title: DNA methylation and mono-allelic gene expression in breast cancer
Project description: The Ohio State Integrative Cancer Biology Program (ICBP) is focused on the development of experimental and computational methods to investigate the role of aberrant epigenetic modifications in carcinogenesis. Epigenetic changes are molecular alterations of chromatin, DNA and its protein packaging system, which do not involve changes in nucleotide sequences. DNA methylation is a common epigenetic mark that regulates cellular differentiation and plays a role in the development of cancer.
Using next generation sequencing, we have generated genome-wide DNA methylation profiles for the ICBP-43 panel of breast cancer cell lines. The proposed summer project will investigate the DNA methylation signatures of chromosomal regions subject to mono-allelic gene expression. Altered gene dosage or disruption of the molecular systems underlying allele-specific expression can have deleterious effects on cellular function and are common to many cancer types. The student will (1) use bioinformatics tools to identify and to analyze DNA methylation patterns of mono-allelic gene loci, (2) correlate methylation patterns with cellular phenotypes, (3) validate results by PCR-based DNA methylation sequencing assays.
Primary field of study: Practical bioinformatics, wet lab
Requirements: Prerequisite coursework: one course in statistics or calculus, two or more upper division courses in cell biology, molecular biology, genetics, or biochemistry; prior experience in a molecular biology lab (or practical lab course); programming or bioinformatics experience are strongly encouraged and may substitute for laboratory experience.
Key words: Epigenetics, DNA methylation, next generation sequencing, breast cancer, mono-allelic gene expression.
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St. Elizabeth’s Medical Center/Tufts University
Boston, MA
Website: http://www.cancer-systems-biology.org
Principal Investigator: Lynn Hlatky, Ph.D.
Mentors: Heiko Enderling, Ph.D.
Julia Fox, Ph.D.
Duration of Program: June 6 through August 5, 2011
Title: Characterizing the regenerative potential of irradiated cancer cell populations
Project description: Of interest to both basic and translational cancer research is idea that cancer ‘stem’ cells (those cancer cells capable of initiating tumor growth or post-therapy regrowth) are a small, but highly resistant, subpopulation of any cancer cell population. We investigate how radiation exposure changes the overall character of a cancer population with respect to enrichment of ‘stem’ versus non-stem compartments, thereby altering the tumor growth potential of the population. Cancer populations will be irradiated and the surviving cell subpopulation characterized for regenerative potential. Through this investigation, the student, working with the mentoring team, will gain exposure to a panel of multiscale approaches to analyze cancer populations: including molecular characterization using Illumina gene array platforms, RT PCR and immunohistochemical analysis of surface markers, in vitro cell kinetic studies, and in vivo tumor growth studies. In turn, these studies will provide straightforward parameter values for improvement of our ongoing agent-based modeling (ABM) effort, allowing, in addition to the wet-lab work, the opportunity for the student to gain exposure to computational models of tumor-development.
Requirements: General experience in a biological laboratory setting desirable.
Keywords: Cancer stem cells, radiation, cell culture, in vitro culture, in vivo tumor models, gene arrays, agent-based modeling, data analysis and presentation.
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Stanford University School of Medicine
Palo Alto, CA
Website: http://icbp.stanford.edu
Principal Investigator: Sylvia Plevritis, Ph.D.
Mentor: Ash Alizadeh, Ph.D.
Duration of Program: approximately June 19 through August 19, 2011
Title: siRNA-targeting of genes associated with lymphoma transformation and progression
Project description: Follicular lymphoma is a malignancy of B-cells, which although usually slow in progression, is incurable. In many patients, follicular lymphoma transforms into a much more aggressive diffuse large B-cell lymphoma. The clinical course of the disease accelerates drastically, and most patients die within a year. We have previously identified a set of genes that appear to be driven by the developmental regulator EZH2, and which may be central in driving the transformation process. Targeting these genes represents a possible therapeutic treatment and will further understanding of the transformation process.
The aim of this project is to manipulate lymphoma cell lines using interfering RNA (siRNA) to determine the effect on their phenotype of targeting EZH2-related genes. The student will learn the procedures for culturing and growing the cell lines, and how to perform siRNA experiments in them and assess the effect on their phenotype such as apoptosis, growth rates etc.
Experience with basic molecular biology experimental methods is a requirement - cell culturing and knowledge of the principles of siRNA would be very useful. Some familiarity with analyzing high-throughput data such as gene expression would be a plus. Depending on the student's background and interest in computational methods (e.g., programming in R, or using expression data analysis packages), the project could also involve looking at large lymphoma datasets to better understand the role of the EZH2 module in transformation.
Requirements: Experience with basic molecular biology methods, and at least some knowledge of siRNA
Keywords: Cell lines, siRNA, lymphoma, cancer progression
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Vanderbilt University Medical Center
Nashville, TN
Website: http://vicbc.vanderbilt.edu/ccsb/
Principal Investigator: Vito Quaranta, M.D.
Mentors: Darren Tyson, Ph.D.
Shawn Garbett, M.S.
Duration of program: Wednesday June 1st (check in the dorm on Tuesday, May 31st) and end on Friday, August 5th (check out of the dorm on Saturday, August 6th).
Title: Population dynamics of cancer cell cycle proliferation in response to drugs
Project description: Cancer is primarily a disease of unrestrained cellular proliferation. It is now understood that even cells with the same genetic background can respond differently to the same stimulus yet little is known about how individual cells make decisions to progress through the cell cycle. Recent technological advances have now made it possible to obtain information about cell cycle progression at the single cell level and these rich data sets are providing a wealth of new information about how benign and cancerous cells make these decisions. We will use fluorescent time lapse microscopic imaging of human cell lines to investigate population dynamics of cell cycle progression in response to drug treatment. Cells with fluorescent tags will be imaged and cell age and cell cycle states will be manually or automatically extracted. The data will then be fit to one or more mathematical models to help understand the underlying biology.
Primary field of study: The student may be involved in any or all aspects of this project, depending on background and interest, including: cell culture, live cell fluorescent microscopic imaging, image processing, statistical data analysis, and mathematical modeling.
Requirements: Useful experience would include: cell culture; fluorescence microscopy, image processing using Matlab or ImageJ, familiarity with the statistical analysis program R, and an understanding of the mammalian cell cycle.
