Metastatic melanoma is the deadliest form of skin cancer and one of the most aggressive cancer types, capable of rapid spreading out ofthe primary site. This proposal Is aimed at analyzing the combined effect of changes in the genetic and signaling states of melanoma cells and the cell micro-environment on the the degree of cell aggressiveness and putative metastatic potential. The main hypothesis underlying our analysis is that aggressiveness of melanoma cells is determined by a combination of different factors, with a major contribution from the state of cell microenvironment, including the structure ofthe ECM and the presence of soluble chemical factors. Alteration in the cell micro-environment, such as alignment of ECM fibers, can permit an othenwise non-metastatic cell to become more aggressive, whereas the aggressiveness of ostensibly metastatic cell can be moderated by environmental changes and targeted intervention in regulation of signaling cascades. We also hypothesize that cells can actively interact with the micro-environment not only by secreting or degrading ECM components, but by actively exercising forces on and thus aligning ECM fibers in the direction of a nearest anchor point, including the vasculature. This can in turn generate more anisotropic forces allowing cells to deform ECM even more and ultimately take advantage ofthe re-aligned ECM structure to migrate towards blood vessels. We will test these hypotheses in close collaboration with ICBP@MIT, first taking advantage ofthe new methodologies using shRNA libraries to perturb genetic targets (Aim 1) along with a broad range of environmental perturbations and then use the state of the art statistical analysis tools available at ICBP(gMIT to reduce complexity of resulting datasets, linking multiple environmental and genetic perturbation to aggressive cell behavior (Aim 2), We will use several novel assays in the process, increasing manageability of data acquisition and processing, as well as enhancing the biomimetic nature of experimentation. Finally, we will test the predictions arising from the models developed in Aim 2 through a series of tests, ranging from cell culture to tissue construct to model tissue levels (Aim 3). We anticipate that the proposed research will reveal new, previously unanticipated interplay between environmental and genetic factors in control of metastatic events in melanoma and potentially suggest new ways of battling this deadly disease. The results might also have relevance to other metastatic cancers.

Public Health Relevance

Early detection is further hampered by the lack of biomarker-based detection tests. One ofthe critical reasons for this situation is the lack of understanding ofthe mechanisms underlying the metastatic switch in melanoma and the mechanisms allowing metastatic cells to successfully and quickly navigate all the hurdles associated with the metastatic spread, including effective migration to and intravasation into the blood vessels. This project is aimed at filling this critical gap.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA155758-02
Application #
8333984
Study Section
Special Emphasis Panel (ZCA1-SRLB-V (O1))
Program Officer
Li, Jerry
Project Start
2011-09-16
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$400,424
Indirect Cost
$122,026
Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Holmes, William R; Park, JinSeok; Levchenko, Andre et al. (2017) A mathematical model coupling polarity signaling to cell adhesion explains diverse cell migration patterns. PLoS Comput Biol 13:e1005524
Park, JinSeok; Holmes, William R; Lee, Sung Hoon et al. (2017) Mechanochemical feedback underlies coexistence of qualitatively distinct cell polarity patterns within diverse cell populations. Proc Natl Acad Sci U S A 114:E5750-E5759
Wilson, Jennifer L; Dalin, Simona; Gosline, Sara et al. (2016) Pathway-based network modeling finds hidden genes in shRNA screen for regulators of acute lymphoblastic leukemia. Integr Biol (Camb) 8:761-74
Mugler, Andrew; Levchenko, Andre; Nemenman, Ilya (2016) Limits to the precision of gradient sensing with spatial communication and temporal integration. Proc Natl Acad Sci U S A 113:E689-95
Smith, Chris L; Kilic, Onur; Schiapparelli, Paula et al. (2016) Migration Phenotype of Brain-Cancer Cells Predicts Patient Outcomes. Cell Rep 15:2616-24
Park, JinSeok; Kim, Deok-Ho; Kim, Hong-Nam et al. (2016) Directed migration of cancer cells guided by the graded texture of the underlying matrix. Nat Mater 15:792-801
Lin, Benjamin; Yin, Taofei; Wu, Yi I et al. (2015) Interplay between chemotaxis and contact inhibition of locomotion determines exploratory cell migration. Nat Commun 6:6619
Cheung, Kevin J; Ewald, Andrew J (2014) Illuminating breast cancer invasion: diverse roles for cell-cell interactions. Curr Opin Cell Biol 30:99-111
Huebner, Robert J; Ewald, Andrew J (2014) Cellular foundations of mammary tubulogenesis. Semin Cell Dev Biol 31:124-31
Cheung, Kevin J; Gabrielson, Edward; Werb, Zena et al. (2013) Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155:1639-51

Showing the most recent 10 out of 14 publications