Seminar Series

Reconstructing Signaling Networks in Breast Cancer Cell Lines

Friday August 23rd at 11 am (Li Ka Shing Center, Rm LK 101)
Paul Spellman, Associate Professor, Oregon Health & Science University

TBD

Friday September 20th at 11 am (Li Ka Shing Center)
Kevin White, Professor of Human Genetics, University of Chicago

Stratifying cancer into subtypes using knowledge of molecular networks

Friday October 18th at 11 am (Li Ka Shing Center)
Trey Ideker, Chief of Medical Genetics, UC San Diego

Many types of cancer are stratified into multiple subtypes with differing molecular causes. Somatic tumor genomes provide a rich new source of data for identifying these subtypes, but they have proven difficult to compare as two tumors rarely share the same mutations. Here, we introduce a method called 'network-based stratification' which integrates somatic tumor genomes with gene networks. This approach allows for stratification of cancer into informative subtypes by clustering together patients who have mutations within similar network regions. We show that network-based stratification of ovarian tumor exomes results in subtypes that are predictive of patient survival and response to therapy, in contrast to subtypes based on other types of molecular profiles. The most aggressive subtype associates specifically with mutations in networks related to the Fibroblast Growth Factor Receptor, the nucleoskeleton, caspases, and protein transport. Subtypes are used to train an mRNA expression signature which provides similar information in the absence of DNA
sequence.

TBD

Friday November 15th at 11 am (Li Ka Shing Center)
Sourav Bandyopadhyay, Helen Diller Family Comprehensive Cancer Center, UCSF

Cell-to-cell variability in T lymphocyte signaling: molecular underpinning and functional significance

Friday April 26th at 11 am (Li Ka Shing Center, Rm LK 101)
Grégoire Altan-Bonnet, Associate Professor, Memorial Sloan-Kettering Cancer Center

Next-generation sequencing approaches for studying tumor evolution and heterogeneity

Friday March 15th at 11 am (Li Ka Shing Center, Rm LK 101)
Olivier Elemento, Assistant Professor, Physiology and Biophysics, Cornell University

Cancer is a fundamentally Darwinian process where millions of genetically and epigenetically heterogeneous tumor cells compete in the presence of diverse and changing selective pressures imposed by the cells themselves, the microenvironment and treatment, e.g. chemotherapy. As illustrated by the nearly systematic acquisition of resistance in patients treated with targeted anticancer agents, this Darwinian process presents formidable challenges for cancer therapy.

In the first part of the talk, I will describe our attempts to study clonal heterogenity and tumor evolution at the genomic and epigenomic level in B cell lymphomas. As their name indicates, B cell lymphomas originate from B cells,which undergo a unique process of VDJ recombination and somatic hypermutation. These unique features of B cells and B cell lymphomas effectively tag clonal populations of tumor cells. I will show how the combination of high-throughput sequencing of VDJ junctions and exome sequencing provides unique insights into clonal heterogeneity and evolutionary patterns in patients with relapsed lymphoma. I will describe additional new insights on the epigenomic evolution of lymphomas.

In the second part of the talk, I will describe how the Darwinian process that drives populations of tumor cells also provides key opportunities for unraveling mechanisms of action and targets of anticancer molecules directly in human cells. I will present an unbiased, genomewide approach that combines next-generation sequencing and bioinformatic analysis for identification of these mechanisms of action. This approach is based on the isolation of multiple drug resistant clones and rapid sequencing using RNA-seq. Importantly, this approach can identify mechanisms of resistance to anticancer drugs long before any patients are treated with these molecules, thus paving the way for pre-treatment genotyping of patients. It also predicts combinations of drugs that should slow down or prevent the acquisition of resistance.

Widespread Epigenetic Alterations in Aging Hematopoietic Stem Cells

Monday February 11th at 4 pm (Clark Center Auditorium)
Margaret Goodell, Stem Cells and Regenerative Medicine, Baylor College of Medicine

Stem-like states and phenotypic transitions in cancer

Friday February 1st at 11 am (Li Ka Shing Center, Rm LK101)
Piyush Gupta, Assistant Professor of Biology, MIT

Cancer cells exist in distinct phenotypic states that resemble differentiation programs operative in the normal tissue type from they derive. Phenotypic states differ with respect to their malignant properties with stem-like states being primarily responsible for tumor
dissemination and therapy resistance. Cancer cells can transition between phenotypic states, including bidirectional interconversion between stem-like and non-stem-like states. This presentation will describe novel small molecule, shRNA and computational approaches that are being applied to characterize phenotypic states and model transitions between them.

Connecting Genetics to Phenotype using quantitative proteomics

Friday January 11th at 12 pm (Li Ka Shing Center, Rm LK 130)
Forest White, Associate Professor, Biological Engineering, MIT

Over the past 5+ years, there have been extensive efforts by multiple groups to characterize genetic aberrations in human cancers and other common diseases.  While these studies have led to very large scale datasets and have identified many common mutations, in most cases the mechanistic connection between genetic aberration and disease phenotype is poorly understood.  To uncover the mechanisms by which genetic alterations drive oncogenic phenotypes, we have developed a quantitative mass spectrometry based approach to map signaling networks in a broad variety of biological samples, from cell lines to mammalian tissues.  To effectively monitor protein phosphorylation events governing signaling cascades, our approach enables the simultaneous quantification of tyrosine phosphorylation of specific residues on dozens of proteins at multiple time points under a variety of perturbations.  We have applied this technique to identify key signaling nodes regulating EGFR, Insulin Receptor, and T Cell Receptor signaling network response to stimulation.  Using this technology, we have performed an in-depth characterization of signaling networks in glioblastoma human tumor xenografts and flash-frozen human glioblastoma tumors.  We have quantified expression for thousands of proteins and several hundred tyrosine phosphorylation sites across 8 tumor xenografts with a range of wtEGFR or EGFRvIII expression, with four replicates per xenograft.  At the protein expression level, we have identified a small number of proteins that correlate with wtEGFR or EGFRVIII expression and may represent the downstream effect of EGFRvIII expression in these xenografts.  At the pTyr signaling level, the protein tyrosine phosphorylation sites do not cluster with regard to wtEGFR or EGFRvIII expression, and instead highlight multiple different potential driver kinases and pathways within the various tumor xenografts.  Similar efforts are now underway for 21 flash-frozen human glioblastoma tumor specimens.