Cancer is classically modeled as a malignant transformation with genetic mutation of oncogenes or tumor suppressor genes driving uncontrolled cellular growth. However, epigenetic or even stochastic endogenous variations in the expression levels of these genes may be sufficient to disregulate proliferation and apoptosis pathways, and drive tumorigenesis. Thus, there may exist cancers whose origin and maintenance stem from non-genetic perturbations of normal pathways. In this project, we focus on Chronic Lymphocytic Leukemia (CLL), a lymphoproliferative disease characterized by the clonal expansion of mature B lymphocytes arrested in the G0/G1 phase of the cell cycle. To date, there is no known mutation conferring dominant-positive or dominant negative activities to signaling regulators that would account for the resistance to apoptosis and enhanced proliferation of B cells in CLL. Differential expression of signaling components (e.g. upregulation of CDS and ZAP70) is used to predict clinical prospects for CLL patients, but there is limited understanding of their relevance to the growth dysregulation and disease progression. The goal of this research project is to study the heterogeneity of B cell signaling sustaining proliferation and apoptosis in CLL. For that purpose, we will introduce a systems biology platform that combines theoretical modeling of B cell signaling (under activation by antigens, cytokines or others) with experimental measurements on single primary cells. More specifically, we plan to rely on the natural heterogeneity of B cells (in CLL patients or in healthy individuals), to map out the variability of CLL disease states. We will develop a theoretical biochemical model, to identify key signaling regulators in B cell signaling. We will also apply a new experimental methodology to correlate, at the single cell level, B cell responsiveness with expression levels of these key signaling regulators. Ultimately, we aim at introducing multivariate parameters of individual cells within a population (from markers to functional response) to better characterize CLL phenotypes and offer new therapeutic approaches taking into account the variability in CLL B cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-SRLB-C)
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Korolev, Kirill S; Xavier, Joao B; Gore, Jeff (2014) Turning ecology and evolution against cancer. Nat Rev Cancer 14:371-80
Palomba, M Lia; Piersanti, Kelly; Ziegler, Carly G K et al. (2014) Multidimensional single-cell analysis of BCR signaling reveals proximal activation defect as a hallmark of chronic lymphocytic leukemia B cells. PLoS One 9:e79987
Sevenich, Lisa; Joyce, Johanna A (2014) Pericellular proteolysis in cancer. Genes Dev 28:2331-47
Sevenich, Lisa; Bowman, Robert L; Mason, Steven D et al. (2014) Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat Cell Biol 16:876-88
Pyonteck, Stephanie M; Akkari, Leila; Schuhmacher, Alberto J et al. (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264-72
Chang, Qing; Bournazou, Eirini; Sansone, Pasquale et al. (2013) The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia 15:848-62
Gauthier, Nicholas P; Soufi, Boumediene; Walkowicz, William E et al. (2013) Cell-selective labeling using amino acid precursors for proteomic studies of multicellular environments. Nat Methods 10:768-73
Tkach, Karen; Altan-Bonnet, Gregoire (2013) T cell responses to antigen: hasty proposals resolved through long engagements. Curr Opin Immunol 25:120-5
Cotari, Jesse W; Voisinne, Guillaume; Dar, Orly Even et al. (2013) Cell-to-cell variability analysis dissects the plasticity of signaling of common ? chain cytokines in T cells. Sci Signal 6:ra17
Nadell, Carey D; Bucci, Vanni; Drescher, Knut et al. (2013) Cutting through the complexity of cell collectives. Proc Biol Sci 280:20122770

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