2018 Fiscal Year Research-status Report
Regulatory mechanisms controlling CCL5 chemokine to maintain tissue homeostasis
| Project/Area Number |
18K07186
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
SEO WOOSEOK 国立研究開発法人理化学研究所, 生命医科学研究センター, 研究員 (40574116)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | がん免疫 / ケモカイン / 転写制御 |
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| Outline of Annual Research Achievements |
Chemokines are special proteins which can regulate cell migration within our body. Since immune cell migration is also regulated by chemokines, they are involved in numerous inflammatory diseases. Especially, a kind of chemokine named CCL5 has received a lot of attention lately due to their role in tumorigenesis. However, the molecular mechanisms govern the regulation of CCL5 expression is not known. Therefore, the theme of my research has been to elucidate the molecular mechanisms by which CCL5 expression is regulated, thus leading to better understanding of the physiological significance of CCL5.
The research I performed in the last several years significantly advanced our knowledge on CCL5 regulation. Particularly, the outcomes obtained in this fiscal year showed that CCL5 plays a crucial role during cancer metastasis in our mouse models. This unexpected discovery has been thoroughly analyzed in this fiscal year and the results were presented as an oral and poster presentations at the annual Japanese Society of Immunology. The presentations were well recognized by peers and praised for proposing a new concept. This project has gained significant amounts of data which are enough to be published as a scientific article in the next fiscal year.
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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
Recently, several research papers suggested that CCL5 might play important roles in cancer development in addition to their traditional role as an inflammatory chemokine. My research provides solid evidence that CCL5 indeed functions to modulate cancer microenvironments in which cancer cells and immune cells fight. The outcome of this fight between cancer cells and our immune cells eventually results in either cancer establishment or eradication. Thus, we strongly support the idea that CCL5 can function beyond as a simple chemokine. By using a knockout mouse line I generated in which the constitutive expression of CCL5 is compromised, I found that the properties of immune cells within cancer microenvironments change dramatically, which resulted in stronger anti-cancer immunity. This enhanced anti-cancer immunity was much more efficient in eradication of cancer development in our mice models.
We strongly believe that the research results obtained by this project up to this point can deliver an interesting and novel story to the scientific and medical community. Therefore, we are preparing a manuscript to wrap up the discoveries we made and will submit a manuscript to a respected journal during the first half of the following fiscal year.
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| Strategy for Future Research Activity |
The manuscript we preparing covers the most of outcomes we have obtained in the past several years, but there are several interesting points we would like to further address in the following two years. Especially, I would like to move our attention from our immune system to the cancer cell themselves. Studying how cancer cells behave when attacked by immune cells within cancer microenvironments could give us a new opportunity to develop a way to more efficiently attack cancer cells.
Especially, I found that cancer cells being attacked by immune cells try to escape this anti-cancer immunity by using every resources available to them to survive. They seem to quickly change their cellular properties or even express CCL5 for their own benefits. These various escape mechanisms elicited by cancer cells could have a dire impact on clinical therapies by compromising immuno-therapies which are currently used in clinics. My preliminary results indicated that cancer cells might use a previously unknown mechanism for their own survival by manipulating CCL5 pathways. I plan to study how cancer cells might use CCL5 to improve their survival and try to escape our anti-cancer immunity during the next 2 years.
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| Causes of Carryover |
Several runs of RNA-seq experiments using cancer cells were planned in this fiscal year. However, the knockout mice I generated which were supposed to be used for cancer experiment did not expand to enough numbers. Therefore, I postponed RNA-seq experiments to the next fiscal year.
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Research Products
(2 results)
