This application seeks support for four linked research projects focused on the influences of components of the tumor microenvironment on the progression of primary tumors and metastases using both human tumor materials, cell biological methods and genetically engineered mouse models of cancer, with particular emphasis on breast and lung cancer. The microenvironment of tumors contains many non-tumor cells, including macrophages, neutrophils and myofibroblasts and several of the projects use both mouse models and human patient samples to investigate the influences of these cells on the behavior of the tumor cells - both locally derived as well as systemically recruited cells from the bone marrow and elsewhere (e.g., spleen).The generation and trafficking of these cells will be analyzed using sophisticated in vivo imaging methods in both mouse models and human patients. The secreted signals (growth factors and cytokines) that recruit and program these cells of the """"""""reactive tumor stroma"""""""" will be investigated as will be the mechanisms of their effects on the tumor cells - induction of EMT, acquisition of stem-cell-like properties, migration, invasion, intravasation and extravasation and formation of metastases. The reactive stroma also contains a complex extracellular matrix (ECM), which includes bound growth factors and cytokines and the composition of this ECM changes markedly during tumor progression - these changes will be analyzed in detail using newly developed proteomics methods and their functional significance will be analyzed by manipulating the expression of relevant genes in both tumor and stromal cells. The four project leaders have a history of productive interactions and collaborations that will be further enhanced by TMEN support. The combined use of human patient material to anchor the discoveries to clinically correlated criteria and mouse models for investigation of the causality of the identified interactions in pre-clinical tests will allow progess possible with neither system alone. The common goal of these projects will be to dissect the cellular and non-cellular effects of the tumor stroma on tumor progression with a view to identifying novel biomarkers and signatures of diagnostic and prognostic value and new targets for potential therapeutic intervention.

Public Health Relevance

Tumor cells are strongly influenced by their surroundings, the so-called microenvironment, which contains multiple normal cell types from the local tissue and recruited from distant sites in the body as well an extracellular matrix of proteins. These components interact with tumor cells in both protumorigenic and antitumorigenic ways. This application seeks to identify the roles of many of these microenvironmental influence in cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54CA163109-01
Application #
8212675
Study Section
Special Emphasis Panel (ZCA1-SRLB-3 (O1))
Program Officer
Mohla, Suresh
Project Start
2011-09-23
Project End
2016-07-31
Budget Start
2011-09-23
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$784,417
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Li, Ran; Hebert, Jess D; Lee, Tara A et al. (2017) Macrophage-Secreted TNF? and TGF?1 Influence Migration Speed and Persistence of Cancer Cells in 3D Tissue Culture via Independent Pathways. Cancer Res 77:279-290
Kwan, Byron H; Zhu, Eric F; Tzeng, Alice et al. (2017) Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses. J Exp Med 214:1679-1690
Gocheva, Vasilena; Naba, Alexandra; Bhutkar, Arjun et al. (2017) Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival. Proc Natl Acad Sci U S A 114:E5625-E5634
Engblom, Camilla; Pfirschke, Christina; Zilionis, Rapolas et al. (2017) Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358:
Naba, Alexandra; Clauser, Karl R; Mani, D R et al. (2017) Quantitative proteomic profiling of the extracellular matrix of pancreatic islets during the angiogenic switch and insulinoma progression. Sci Rep 7:40495
Carmona, G; Perera, U; Gillett, C et al. (2016) Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE. Oncogene 35:5155-69
Pfirschke, Christina; Engblom, Camilla; Rickelt, Steffen et al. (2016) Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity 44:343-54
De Cock, Jasmine M; Shibue, Tsukasa; Dongre, Anushka et al. (2016) Inflammation Triggers Zeb1-Dependent Escape from Tumor Latency. Cancer Res 76:6778-6784
Naba, Alexandra; Clauser, Karl R; Ding, Huiming et al. (2016) The extracellular matrix: Tools and insights for the ""omics"" era. Matrix Biol 49:10-24
Spiegel, Asaf; Brooks, Mary W; Houshyar, Samin et al. (2016) Neutrophils Suppress Intraluminal NK Cell-Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells. Cancer Discov 6:630-49

Showing the most recent 10 out of 29 publications