A critical issue in modern cancer research is how diversity, both genetic and non-genetic, influences tumor progression and response to therapy. The Center for Cancer Systems Biology (CCSB) at MSKCC assembles a consortium of investigators who integrate computational and experimental strategies to investigate diversity in cancer at the level of individual cells, tumor microenvironment, and patients. The research program for this CCSB is organized into four inter-related subprojects. (I)We study the variability of cellular responses to growth factors and drugs during tumorigenesis, using competition for the growth factor IL-6 in melanoma and breast cancer cells as a model system. We use computational modeling of the dynamics of the IL-6 pathway in order to optimize new chemotherapeutic protocols that rely on cellular diversity to maximize tumor cytotoxicity. (II) We use expression profiling of protease networks in both tumor and stromal cells and genome-wide profiling of subpopulations of tumor-associated macrophages to learn predictive statistical models of tumor-stromal cell interactions. We also use agent-based computational models to simulate cancer-cell macrophage interactions. Computational predictions will be validated with in vitro and in vivo experiments. (Ill)We focus on predictive network models of differences in signaling information flow in distinct tumor subtypes. Using the results of systematic drug perturbation experiments, we will design Hopfield network models based on non-linear differential equations to decipher the differences in signaling networks between primary glioblastoma subtypes and to investigate the changes in network dynamics during the evolution of drug resistance. (IV) We study the endogenous diversity of B cell signaling pathways in Chronic Lymphocytic Leukemia (CLL) patients. We will generate biochemical models of signaling pathways to identify key signaling regulators whose variation in expression predicts functional heterogeneity, validate the predictions with single-cell profiling, and define a new set of functional markers to better characterize disease progression. By elucidating the consequences of diversity in cancer, this research will ultimately guide the development of new cancer therapies.

Public Health Relevance

The MSKCC CCSB is an interdisciplinary team of investigators with strong clinical links who will use novel 9xperimental-computational methods in systems biology to investigate diversity in cancer at the level of cells, :issues and patients. The research program supports the public health goals ofthe ICBP of NCI through its jitimate impact on the development of new cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA148967-02
Application #
8068280
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (J1))
Program Officer
Gallahan, Daniel L
Project Start
2010-05-01
Project End
2015-02-28
Budget Start
2011-04-25
Budget End
2012-02-29
Support Year
2
Fiscal Year
2011
Total Cost
$2,716,373
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Jena, Prakrit V; Roxbury, Daniel; Galassi, Thomas V et al. (2017) A Carbon Nanotube Optical Reporter Maps Endolysosomal Lipid Flux. ACS Nano 11:10689-10703
Carmona-Fontaine, Carlos; Deforet, Maxime; Akkari, Leila et al. (2017) Metabolic origins of spatial organization in the tumor microenvironment. Proc Natl Acad Sci U S A 114:2934-2939
Vogel, Robert M; Erez, Amir; Altan-Bonnet, Grégoire (2016) Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis. Nat Commun 7:12428
Quail, Daniela F; Bowman, Robert L; Akkari, Leila et al. (2016) The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352:aad3018
Argyropoulos, K V; Vogel, R; Ziegler, C et al. (2016) Clonal B cells in Waldenström's macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling. Leukemia 30:1116-25
Gao, Sizhi P; Chang, Qing; Mao, Ninghui et al. (2016) JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors. Sci Signal 9:ra33
Prill, Robert J; Vogel, Robert; Cecchi, Guillermo A et al. (2015) Noise-driven causal inference in biomolecular networks. PLoS One 10:e0125777
Buffie, Charlie G; Bucci, Vanni; Stein, Richard R et al. (2015) Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517:205-8
Voisinne, Guillaume; Nixon, Briana G; Melbinger, Anna et al. (2015) T Cells Integrate Local and Global Cues to Discriminate between Structurally Similar Antigens. Cell Rep 11:1208-19
Korkut, Anil; Wang, Weiqing; Demir, Emek et al. (2015) Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife 4:

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