The central step in cancer progression that leads to mortality is metastasis, the dissemination of cells from the primary tumor mass to distant organs. Research in the """"""""EMT, Migration and Metastasis Networks"""""""" program is aimed at elucidating the regulatory pathways governing tumor progression to full metastatic disease with the goal of identifying new targets for therapeutic intervention in the treatment of malignant cancers. The proposed research focuses on four general aspects of metastasis: acquisition of a motile phenotype during epithelial to mesenchymal transition (EMT), motility responses to growth factor stimulation, dissemination of metastasis to the CNS and acquisition of resistance to therapy. We will use mathematical modeling to indentify novel regulatory pathways that control cell behavior as tumor cells develop an invasive, metastatic phenotype. Cell behavior during EMT and growth factor elicited motility will be measured quantitatively. The status of signaling pathways, gene expression and alternative splicing wall be interrogated and used to take an integrative systems approach to develop computational, data-driven models that relate these metrics to cell behavior. The models will be used to identify novel regulatory relationships governing the steps in carcinoma metastasis from initial invasion to tumor cell entry into blood or lymphatic vessels. Metastasis often leads to the acquisition of resistance both to conventional chemotherapy and to target treatments, possibly by allowing tumor cells to evade treatment by infiltrating a protected microenvironment such as the central nervous system. Tumor cell targeting of the central nervous system and acquisition of therapy resistant phenotypes will be explored using high-throughput RNAi screening approaches in vivo in a lymphoma model. The research program will employ mammary epithelia cells, breast cancer cells, xenografts and syngeneic tumor models, and lymphoma.

Public Health Relevance

The major causes of death from cancer stem from the spread of the disease from the primary tumor to distant organs. To identify new ways to interfere with cancer dissemination, the status of many cell regulatory systems will be measured and correlated mathematically with changes that cells undergo during cancer progression. The resulting mathematical models can uncover new connections between cell regulation and metastic behavior for the development of new therapies to treat the disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA112967-10
Application #
8619593
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Kulkarni, Madhura; Tan, Tuan Zea; Syed Sulaiman, Nurfarhanah Bte et al. (2018) RUNX1 and RUNX3 protect against YAP-mediated EMT, stem-ness and shorter survival outcomes in breast cancer. Oncotarget 9:14175-14192
Oudin, Madeleine J; Barbier, Lucie; Schäfer, Claudia et al. (2017) MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer. Mol Cancer Ther 16:143-155
Bruno, Peter M; Liu, Yunpeng; Park, Ga Young et al. (2017) A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress. Nat Med 23:461-471
Werbin, Jeffrey L; Avendaño, Maier S; Becker, Verena et al. (2017) Multiplexed Exchange-PAINT imaging reveals ligand-dependent EGFR and Met interactions in the plasma membrane. Sci Rep 7:12150
Miller, Miles A; Sullivan, Ryan J; Lauffenburger, Douglas A (2017) Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer. Clin Cancer Res 23:623-629
Nagel, Zachary D; Kitange, Gaspar J; Gupta, Shiv K et al. (2017) DNA Repair Capacity in Multiple Pathways Predicts Chemoresistance in Glioblastoma Multiforme. Cancer Res 77:198-206
Miller, Miles A; Oudin, Madeleine J; Sullivan, Ryan J et al. (2016) Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance. Cancer Discov 6:382-99
Lescarbeau, Rebecca S; Lei, Liang; Bakken, Katrina K et al. (2016) Quantitative phosphoproteomics reveals Wee1 kinase as a therapeutic target in a model of proneural glioblastoma. Mol Cancer Ther :
Oudin, Madeleine J; Hughes, Shannon K; Rohani, Nazanin et al. (2016) Characterization of the expression of the pro-metastatic Mena(INV) isoform during breast tumor progression. Clin Exp Metastasis 33:249-61
Sun, Daphne; Dalin, Simona; Hemann, Michael T et al. (2016) Differential selective pressure alters rate of drug resistance acquisition in heterogeneous tumor populations. Sci Rep 6:36198

Showing the most recent 10 out of 222 publications