The extracellular matrix (ECM) is known to change markedly during tumor progression and its histological presentation is used as a prognostic indicator by pathologists. It is clear that the ECM provides both structural, physical and biochemical cues to both normal and tumor cells, with major effects on cell proliferation, survival, differentiation and motility - it is also crucial for regulation of angiogenesis. However, we do not have a good understanding of the biochemical composition of the ECM in tissues because of its complexity, crosslinking and insolubility that make biochemical analyses difficult. This group has developed innovative methods for analyzing the in vivo matrix of normal tissues and tumors by combining newly developed bioinformatic analyses of the ECM and ECM-associated proteins encoded in mammalian genomes with state-of-the-art proteomics analyses of ECM-enriched samples from mouse models of cancer and from human patient material from tumor banks. These methods and improvements proposed in this application will be used to investigate the composition and changes in ECM that occur during tumor progression, invasion, angiogenesis and metastasis. The nature and origins (tumor cells or stromal cells) of the tumor ECM will be characterized and associated growth factors and cytokines will be identified. The functional roles of proteins showing interesting changes during tumor progression will be analyzed using loss- and gain-of-function manipulations. These will be implemented using viral vectors developed in prior research by this group that allow manipulation of the levels of gene expression in specific cells either up or down. In addition to shedding light on the mechanisms of function of ECM proteins, these studies may identify targets for intervention in tumor progression. By comparing the profiles of ECM and ECM-associated proteins in human patient samples (normal and tumor tissues) and correlating those results with clinical data on tumor outcomes and response to therapy, it is hoped that it will be possible to identify signatures that will be diagnostic or prognostic.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-SRLB-3)
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Massachusetts Institute of Technology
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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
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
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
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
Roper, Jatin; Tammela, Tuomas; Cetinbas, Naniye Malli et al. (2017) In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis. Nat Biotechnol 35:569-576
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

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