2016 Fiscal Year Annual Research Report
Unraveling the Mechanism behind Cell Motility Enhancement due to Anisotropic Mechanical Signals in Relation to Cancer and Metastasis
| Project/Area Number |
16H05972
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| Research Institution | The University of Tokyo |
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Principal Investigator |
久代 京一郎 東京大学, 大学院工学系研究科(工学部), 助教 (90632539)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Keywords | Cell Migration / Cancer / Microtopography / Mechanotransduction |
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| Outline of Annual Research Achievements |
In my research to understand the effects of material surface topography on cell motility of normal and cancerous cells, we made a couple interesting discoveries in the fiscal year 2016. With the much appreciated research funding by the Grant-in-Aid of Young Scientists (A), we were able to purchase and implement the multi-point incubator-microscope system (AZTEC CCM-1.41IID/C) for cell monitoring, and by utilizing this system, we discovered some intriguing differences between the movement of normal and cancerous cells when they encounter microtopography, which may be important in cell migration processes like cancer metastasis. We found that cancerous cells, due to their broken cytoskeletal organization, do not receive strong signals from the microtopographical structures, and this allows them to even completely ignore the structures and climb over them. This is different from the normal cells that align their cytoskeleton to the microtopographical features, polarize and migrate in that direction. Furthermore, we have gained a deeper understanding of the mechanotransduction within the cells by immunostaining for the focal adhesion components and actin stress fibers. In addition, by utilizing genetically altered cell lines and inhibitory drugs, we were able to identify couple genes that are crucial for this process. The research results described thus far have been turned into a paper, which is currently undergoing post-revision submission in Journal Nature Scientific Reports and should be published soon.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
The progression of research is mostly in line with what was initially planned, where we successfully achieved (1) identification of key mechanotransduction molecules, such as APC and RAS, involved in the topography-directed cell migration of normal and cancerous cells and (2) understand the underlying mechanotransduction behind the topography-directed cell migration movement, where we discovered that focal adhesion patterns and actin alignments were vastly different between normal and cancerous cells. Also, there were some interesting discoveries that linked the migration patterns of normal cells and cancerous cells. For example, when certain changes were made to the mechanotransduction pathways of normal cells, such as inhibiting the myosin II by blebbistatin, they were able to climb over the microgroove walls, a behavior that had previously been only seen in cancerous cells. Thus, overall, we believe that the research is progressing as planned.
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| Strategy for Future Research Activity |
Basic Research Roadmap
1.Now that we have established certain rules for normal and cancer cell migration against microgroove structures, as well as some of the key molecules involved in this phenomena, such as APC, Rho and Rac, we plan to start fabricating non-conventional 3D structures involving angled walls and steps, which may be able to guide certain types of cells to different directions. The fabrication will likely take place in NanoBic at Shin-Kawasaki.
2.There are many other material and surface properties (such as elasticity and adhesivity) that can affect cell migration, so we are investigating the influence of changing these parameters on the topography-directed cell migration. In addition, external directional stimuli, such as fluid flow and chemical gradients, are being integrated into the incubated microscope system using miniature microfluidic pump systems.
3.The mechanotransduction signal pathways involved in this topography-based cell migration will still be further investigated. Specifically, the role of cell polarization, actin organization and membrane protrusions will be probed with drugs such as latranculin, cytochalasin D and Y-27632. Furthermore, gene knockdown using siRNA is also being considered for some protrusion-regulating genes.
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