The goal of this proposal is the development of anti-metastasis therapeutics. To achieve this goal, we propose a novel, multidisciplinary approach that combines nano-technology with molecular and cell biology. The rationale is to deconstruct the directional cell motility mechanisms that underlie invasiveness through control of cell geometry. The premise of the approach is that control of cell geometry will allow us to elicit stereotypical structural and functional cell phenotypes characteristic of defined phases of the motility cycle. Arrays of essentially identical """"""""designer cells"""""""" will provide a unique platform for probing complex directional motility mechanisms and for establishing high-content, translational screening procedures. We will first develop the nano-technology to control the geometry and, therefore, the motility machinery of cells. Technologies will be developed that are compatible with live cell imaging and electron microscopy. Novel technologies will include wet stamping (WETS) to create transparent adhesive islands, controlled etching (GET) to generate nano-patterns from micro-patterns and parallel array dip pen lithography (DPN) to direct write nano-features. Based on this technology, we will then generate patterned substrata, including circles, triangles, tear-drops and polygons surrounded by satellite nano-spots to deconstruct directional motility mechanisms. We will focus on focal adhesion (FA)-microtubule (MT) interaction and focal adhesion turnover;cell polarization and lamellipodial protrusion;filopodial formation and MT interaction;and membrane protease recruitment. Gene silencing in combination with high-content screening of arrays of identical, """"""""designer"""""""" cells will lead to identification of molecular targets and pathways crucial for directional motility. These targets and pathways will then serve as the basis for screens to identify small molecule inhibitors of metastasis.

Public Health Relevance

Lay description: The major cause of death in cancer is from metastasis which depends on the ability of cells to crawl. However, we currently have no approved drugs that target this fundamental process. The proposed research provides the potential to discover a new class of cancer drugs that will inhibit or reduce metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA119341-05
Application #
7932852
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$466,451
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Pillai, Pramod P; Kowalczyk, Bartlomiej; Kandere-Grzybowska, Kristiana et al. (2016) Engineering Gram Selectivity of Mixed-Charge Gold Nanoparticles by Tuning the Balance of Surface Charges. Angew Chem Int Ed Engl 55:8610-4
Chen, Si; Paunesku, Tatjana; Yuan, Ye et al. (2015) The Bionanoprobe: Synchrotron-based Hard X-ray Fluorescence Microscopy for 2D/3D Trace Element Mapping. Micros Today 23:26-29
Vistain, Luke F; Yamamoto, Natsuho; Rathore, Richa et al. (2015) Targeted Inhibition of Snail Activity in Breast Cancer Cells by Using a Co(III) -Ebox Conjugate. Chembiochem 16:2065-72
Zhang, Chuan; Hao, Liangliang; Calabrese, Colin M et al. (2015) Biodegradable DNA-Brush Block Copolymer Spherical Nucleic Acids Enable Transfection Agent-Free Intracellular Gene Regulation. Small 11:5360-8
Dam, Duncan Hieu M; Lee, Hyojin; Lee, Raymond C et al. (2015) Tunable loading of oligonucleotides with secondary structure on gold nanoparticles through a pH-driven method. Bioconjug Chem 26:279-85
Viola, Kirsten L; Sbarboro, James; Sureka, Ruchi et al. (2015) Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease. Nat Nanotechnol 10:91-8
Wilk, Gary; Iwasa, Masatomo; Fuller, Patrick E et al. (2014) Universal area distributions in the monolayers of confluent mammalian cells. Phys Rev Lett 112:138104
Chen, S; Deng, J; Yuan, Y et al. (2014) The Bionanoprobe: hard X-ray fluorescence nanoprobe with cryogenic capabilities. J Synchrotron Radiat 21:66-75
Wu, Xiaochen A; Choi, Chung Hang J; Zhang, Chuan et al. (2014) Intracellular fate of spherical nucleic acid nanoparticle conjugates. J Am Chem Soc 136:7726-33
Kurepa, Jasmina; Nakabayashi, Ryo; Paunesku, Tatjana et al. (2014) Direct isolation of flavonoids from plants using ultra-small anatase TiO? nanoparticles. Plant J 77:443-53

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