Overall Over 90% of cancer related mortality is linked to invasive and metastatic spread of cancer cells from the primary tumor. This spread can be catastrophically fast in the cases of particularly aggressive, high grade melanomas and gliomas (i.e., glioblastoma multiforme (GBM)), leading to uniformly poor prognosis and short life expectancy in these cancers. In spite of the crucial importance of invasive cancer phenotype, we still have only fragmentary knowledge and understanding of the mechanisms leading to transition from proliferative to aggressive, migratory behavior of cancer cells (referred here as the P-A phenotypic switch). Increasing evidence suggests that this switch is a reflection of inherent capacity of cancer cells to adopt both proliferative and migrator phenotypes, with the probability and rate of switching between these two phenotypes controlled by the cell genome, environmental conditions and cell-cell interactions. To address the problem of regulation of invasive cancer spread and, more specifically the P-A phenotypic switch, we propose to establish the Yale Cancer Systems Biology Center (Y-CSBC). The Center will based on the existing organization and infrastructure of the recently founded Yale Systems Biology Institute (YSBI) on the Yale West Campus, leveraging the extensive existing shared resources and juxtaposition of the labs within the same recently renovated, state of the art research space. The Center will bring together researchers from 7 Yale departments based at Yale schools of Arts and Science, Engineering and Applied Science and Medicine and Emory University, in close collaboration with Yale Cancer Institute (physically adjacent to YSBI), Yale Cancer Center, Yale skin cancer SPORE, and Yale Neurosurgery department. The work at the proposed Center will be initially based on the Proposed tightly knit two Research Projects and two support shared resource Cores, initially focused on the analysis of glioblastoma and melanoma cells, and normal cells of various species modeling invasive growth behavior and phenotypic switching. With time, the emphasis on these two cancers may broaden with new members expanding the scope and the aims. The proposed research already reflects the diversity and innovative nature of the work pursued by the participating labs within YSBI and collaborative labs, with the combination of techniques and approaches as diverse as synthetic biology, nano-scale bioengineering, evolutionary biology, high throughput genomics, mathematical modeling, novel animal models, all combined into a integrated research program. The work will be supported by the Administrative Core and the results disseminated through various mechanisms mediated by the Outreach and Education Core. The orthogonal and unconventional approaches proposed in the application and characteristic of the highly collaborative use of cutting edge, innovative approaches, many of which are being pioneered here, will provide an opportunity to advance our understanding of the molecular networks controlling invasive, aggressive cancer spread and lead to new approaches to controlling and treating highly invasive and metastatic malignancies.

Public Health Relevance

Overall Invasion of aggressive cancer cells in various high grade, advanced cancers, particularly glioblastoma multiforme and melanoma, and leading to vast majority of cancer related deaths, is a complex process requiring quantitate, systems approaches for understanding analysis and ultimate prevention. Here is we propose to establish the Yale Cancer Systems Biology Center (Y-CSBC) focused on using highly innovative interdisciplinary approaches to understanding invasive cancer spread, involving tight collaboration between researchers from multiple labs and departments, most of whom will be juxtaposed within the same, state of the art research space. The pioneering research proposed in the application will provide the first comprehensive, systems-level analysis of molecular networks controlling cell transition to invasive, migratory behavior, and will suggest new approaches to clinical interventions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54CA209992-01
Application #
9186335
Study Section
Special Emphasis Panel (ZCA1-RTRB-R (M1))
Program Officer
Hughes, Shannon
Project Start
2016-08-08
Project End
2021-07-31
Budget Start
2016-08-08
Budget End
2017-07-31
Support Year
1
Fiscal Year
2016
Total Cost
$1,990,393
Indirect Cost
$770,401
Name
Yale University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chatterjee, Meenakshi; Acar, Murat (2018) Heritable stress response dynamics revealed by single-cell genealogy. Sci Adv 4:e1701775
Ye, Lupeng; Wang, Chengkun; Hong, Lingjuan et al. (2018) Programmable DNA repair with CRISPRa/i enhanced homology-directed repair efficiency with a single Cas9. Cell Discov 4:46
Chow, Ryan D; Chen, Sidi (2018) Cancer CRISPR Screens In Vivo. Trends Cancer 4:349-358
Xue, Yuan; Acar, Murat (2018) Mechanisms for the epigenetic inheritance of stress response in single cells. Curr Genet 64:1221-1228
Luo, Xinyue; Song, Ruijie; Acar, Murat (2018) Multi-component gene network design as a survival strategy in diverse environments. BMC Syst Biol 12:85
Chow, Ryan D; Chen, Sidi (2018) Sno-derived RNAs are prevalent molecular markers of cancer immunity. Oncogene 37:6442-6462
Chow, Ryan D; Kim, Hyunu Ray; Chen, Sidi (2018) Programmable sequential mutagenesis by inducible Cpf1 crRNA array inversion. Nat Commun 9:1903
Gaines, J C; Acebes, S; Virrueta, A et al. (2018) Comparing side chain packing in soluble proteins, protein-protein interfaces, and transmembrane proteins. Proteins 86:581-591
Elison, Gregory L; Xue, Yuan; Song, Ruijie et al. (2018) Insights into Bidirectional Gene Expression Control Using the Canonical GAL1/GAL10 Promoter. Cell Rep 25:737-748.e4
Vanaja, Kiran G; Timp, Winston; Feinberg, Andrew P et al. (2018) A Loss of Epigenetic Control Can Promote Cell Death through Reversing the Balance of Pathways in a Signaling Network. Mol Cell 72:60-70.e3

Showing the most recent 10 out of 27 publications