During tumorigenesis, cancer cells as well as healthy cells depend upon growth factors produced in an autocrine and paracrine manner to maintain their proliferation and differentiation. Hence there exists a "tug-of war" for growth factors between a tumor and the surrounding non-cancer cells, and the fitness of each individual cell must be defined by this competition at the population level. Importantly, cancer cells on the leading edge of tumors are characterized as being chemo-resistant, have enhanced metastatic potential and are extremely efficient at forming new tumors [6]. We have determined that cancer cells and adjacent stromal cells express high levels of the growth factor IL-6 and activated Stat3 which are hypothesized to be the principal mediators of both tumorigenesis and metastatic progression. In this proposal, we focus on the IL-6/pStat3 pathway in melanoma and breast cancer cells, whose proliferation and differentiation critically depends on pStat3 signals. In the context of understanding tumor dynamics, especially during drug treatment, the intraclonal competition for growth factors within a genetically-idenfical population of cells will be investigated. An understanding of the resulting phenotypic diversity of tumor cells will lead to improved therapeutic interventions eradicating tumor populations. Specifically, we will (1) characterize the variable response of tumor cells to growth factors and targeted inhibitors: (2) design a mathematical framework to predict the consequences of cellular diversity and identify the optimum therapeutic intervention that maximizes the chance of eradicating the tumor;and (3) validate the predictions of the mathematical framework in cell lines and murine models. This project fully leverages our expertise in cancer biology and clinical experience (Bromberg), single cell profiling and biochemical modeling (Altan-Bonnet), and mathematical modeling (Michor). We will dissect how the IL-6 pathway can generate phenotypic variability in tumors, which drives their progression and causes resistance to targeted therapies [7- 13]. Based on our models, we will identify and test the optimal therapeutic protocol for treating these cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA148967-04
Application #
8468142
Study Section
Special Emphasis Panel (ZCA1-SRLB-C)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$544,916
Indirect Cost
$256,372
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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

Showing the most recent 10 out of 14 publications