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KAIST presents a fundamental technology to remove metastatic traits from lung cancer cells
KAIST (President Kwang Hyung Lee) announced on January 30th that a research team led by Professor Kwang-Hyun Cho from the Department of Bio and Brain Engineering succeeded in using systems biology research to change the properties of carcinogenic cells in the lungs and eliminate both drug resistance and their ability to proliferate out to other areas of the body. As the incidences of cancer increase within aging populations, cancer has become the most lethal disease threatening healthy life. Fatality rates are especially high when early detection does not happen in time and metastasis has occurred in various organs. In order to resolve this problem, a series of attempts were made to remove or lower the ability of cancer cells to spread, but they resulted in cancer cells in the intermediate state becoming more unstable and even more malignant, which created serious treatment challenges. Professor Kwang-Hyun Cho's research team simulated various cancer cell states in the Epithelial-to-Mesenchymal Transition (EMT) of lung cancer cells, between epithelial cells without metastatic ability and mesenchymal cells with metastatic ability. A mathematical model of molecular network was established, and key regulators that could reverse the state of invasive and drug resistant mesenchymal cells back to the epithelial state were discovered through computer simulation analysis and molecular cell experiments. In particular, this process succeeded in properly reverting the mesenchymal lung cancer cells to a state where they were sensitive to chemotherapy treatment while avoiding the unstable EMT hybrid cell state in the middle process, which had remained a difficult problem. The results of this research, in which KAIST Ph.D. student Namhee Kim, Dr. Chae Young Hwang, Researcher Taeyoung Kim, and Ph.D. student Hyunjin Kim participated, were published as an online paper in the international journal “Cancer Research” published by the American Association for Cancer Research (AACR) on January 30th. (Paper title: A cell fate reprogramming strategy reverses epithelial-to-mesenchymal transition of lung cancer cells while avoiding hybrid states) Cells in an EMT hybrid state, which are caused by incomplete transitions during the EMT process in cancer cells, have the characteristics of both epithelial cells and mesenchymal cells, and are known to have high drug resistance and metastatic potential by acquiring high stem cell capacity. In particular, EMT is further enhanced through factors such as transforming growth factor-beta (TGF-β) secreted from the tumor microenvironment (TME) and, as a result, various cell states with high plasticity appear. Due to the complexity of EMT, it has been very difficult to completely reverse the transitional process of the mesenchymal cancer cells to an epithelial cell state in which metastatic ability and drug resistance are eliminated while avoiding the EMT hybrid cell state with high metastatic ability and drug resistance. Professor Kwang-Hyun Cho's research team established a mathematical model of the gene regulation network that governs the complex process of EMT, and then applied large-scale computer simulation analysis and complex system network control technology to identify and verify 'p53', 'SMAD4', and 'ERK1' and 'ERK 2' (collectively ERKs) through molecular cell experiments as the three key molecular targets that can transform lung cancer cells in the mesenchymal cell state, reversed back to an epithelial cell state that no longer demonstrates the ability to metastasize, while avoiding the EMT hybrid cell state. In particular, by analyzing the molecular regulatory mechanism of the complex EMT process at the system level, the key pathways were identified that were linked to the positive feedback that plays an important role in completely returning cancer cells to an epithelial cell state in which metastatic ability and drug resistance are removed. This discovery is significant in that it proved that mesenchymal cells can be reverted to the state of epithelial cells under conditions where TGF-β stimulation are present, like they are in the actual environment where cancer tissue forms in the human body. Abnormal EMT in cancer cells leads to various malignant traits such as the migration and invasion of cancer cells, changes in responsiveness to chemotherapy treatment, enhanced stem cell function, and the dissemination of cancer. In particular, the acquisition of the metastatic ability of cancer cells is a key determinant factor for the prognosis of cancer patients. The EMT reversal technology in lung cancer cells developed in this research is a new anti-cancer treatment strategy that reprograms cancer cells to eliminate their high plasticity and metastatic potential and increase their responsiveness to chemotherapy. Professor Kwang-Hyun Cho said, "By succeeding in reversing the state of lung cancer cells that acquired high metastatic traits and resistance to drugs and reverting them to a treatable epithelial cell state with renewed sensitivity to chemotherapy, the research findings propose a new strategy for treatments that can improve the prognosis of cancer patients.” Professor Kwang-Hyun Cho's research team was the first to present the principle of reversal treatment to revert cancer cells to normal cells, following through with the announcement of the results of their study that reverted colon cancer cells to normal colon cells in January of 2020, and also presenting successful re-programming research where the most malignant basal type breast cancer cells turned into less-malignant luminal type breast cancer cells that were treatable with hormonal therapies in January of 2022. This latest research result is the third in the development of reversal technology where lung cancer cells that had acquired metastatic traits returned to a state in which their metastatic ability was removed and drug sensitivity was enhanced. This research was carried out with support from the Ministry of Science and ICT and the National Research Foundation of Korea's Basic Research in Science & Engineering Program for Mid-Career Researchers. < Figure 1. Construction of the mathematical model of the regulatory network to represent the EMT phenotype based on the interaction between various molecules related to EMT. (A) Professor Kwang-Hyun Cho's research team investigated numerous literatures and databases related to complex EMT, and based on comparative analysis of cell line data showing epithelial and mesenchymal cell conditions, they extracted key signaling pathways related to EMT and built a mathematical model of regulatory network (B) By comparing the results of computer simulation analysis and the molecular cell experiments, it was verified how well the constructed mathematical model simulated the actual cellular phenomena. > < Figure 2. Understanding of various EMT phenotypes through large-scale computer simulation analysis and complex system network control technology. (A) Through computer simulation analysis and experiments, Professor Kwang-Hyun Cho's research team found that complete control of EMT is impossible with single-molecule control alone. In particular, through comparison of the relative stability of attractors, it was revealed that the cell state exhibiting EMT hybrid characteristics has unstable properties. (B), (C) Based on these results, Prof. Cho’s team identified two feedbacks (positive feedback consisting of Snail-miR-34 and ZEB1-miR-200) that play an important role in avoiding the EMT hybrid state that appeared in the TGF-β-ON state. It was found through computer simulation analysis that the two feedbacks restore relatively high stability when the excavated p53 and SMAD4 are regulated. In addition, molecular cell experiments demonstrated that the expression levels of E-cad and ZEB1, which are representative phenotypic markers of EMT, changed similarly to the expression profile in the epithelial cell state, despite the TGF-β-ON state. > < Figure 3. Complex molecular network analysis and discovery of reprogramming molecular targets for intact elimination of EMT hybrid features. (A) Controlling the expression of p53 and SMAD4 in lung cancer cell lines was expected to overcome drug resistance, but contrary to expectations, chemotherapy responsiveness was not restored. (B) Professor Kwang-Hyun Cho's research team additionally analyzed computer simulations, genome data, and experimental results and found that high expression levels of TWIST1 and EPCAM were related to drug resistance. (C) Prof. Cho’s team identified three key molecular targets: p53, SMAD4 and ERK1 & ERK2. (D), (E) Furthermore, they identified a key pathway that plays an important role in completely reversing into epithelial cells while avoiding EMT hybrid characteristics, and confirmed through network analysis and attractor analysis that high stability of the key pathway was restored when the proposed molecular target was controlled. > < Figure 4. Verification through experiments with lung cancer cell lines. When p53 was activated and SMAD4 and ERK1/2 were inhibited in lung cancer cell lines, (A), (B) E-cad protein expression increased and ZEB1 protein expression decreased, and (C) mesenchymal cell status including TWIST1 and EPCAM and gene expression of markers related to stem cell potential characteristics were completely inhibited. In addition, (D) it was confirmed that resistance to chemotherapy treatment was also overcome as the cell state was reversed by the regulated target. > < Figure 5. A schematic representation of the research results. Prof. Cho’s research team identified key molecular regulatory pathways to avoid high plasticity formed by abnormal EMT of cancer cells and reverse it to an epithelial cell state through systems biology research. From this analysis, a reprogramming molecular target that can reverse the state of mesenchymal cells with acquired invasiveness and drug resistance to the state of epithelial cells with restored drug responsiveness was discovered. For lung cancer cells, when a drug that enhances the expression of p53, one of the molecular targets discovered, and inhibits the expression of SMAD4 and ERK1 & ERK2 is administered, the molecular network of genes in the state of mesenchymal cells is modified, eventually eliminating metastatic ability and it is reprogrammed to turn into epithelial cells without the resistance to chemotherapy treatments. >
Connecting the Dots to Find New Treatments for Breast Cancer
Systems biologists uncovered new ways of cancer cell reprogramming to treat drug-resistant cancers Scientists at KAIST believe they may have found a way to reverse an aggressive, treatment-resistant type of breast cancer into a less dangerous kind that responds well to treatment. The study involved the use of mathematical models to untangle the complex genetic and molecular interactions that occur in the two types of breast cancer, but could be extended to find ways for treating many others. The study’s findings were published in the journal Cancer Research. Basal-like tumours are the most aggressive type of breast cancer, with the worst prognosis. Chemotherapy is the only available treatment option, but patients experience high recurrence rates. On the other hand, luminal-A breast cancer responds well to drugs that specifically target a receptor on their cell surfaces, called estrogen receptor alpha (ERα). KAIST systems biologist Kwang-Hyun Cho and colleagues analyzed the complex molecular and genetic interactions of basal-like and luminal-A breast cancers to find out if there might be a way to switch the former to the latter and give patients a better chance to respond to treatment. To do this, they accessed large amounts of cancer and patient data to understand which genes and molecules are involved in the two types. They then input this data into a mathematical model that represents genes, proteins and molecules as dots and the interactions between them as lines. The model can be used to conduct simulations and see how interactions change when certain genes are turned on or off. “There have been a tremendous number of studies trying to find therapeutic targets for treating basal-like breast cancer patients,” says Cho. “But clinical trials have failed due to the complex and dynamic nature of cancer. To overcome this issue, we looked at breast cancer cells as a complex network system and implemented a systems biological approach to unravel the underlying mechanisms that would allow us to reprogram basal-like into luminal-A breast cancer cells.” Using this approach, followed by experimental validation on real breast cancer cells, the team found that turning off two key gene regulators, called BCL11A and HDAC1/2, switched a basal-like cancer signalling pathway into a different one used by luminal-A cancer cells. The switch reprograms the cancer cells and makes them more responsive to drugs that target ERα receptors. However, further tests will be needed to confirm that this also works in animal models and eventually humans. “Our study demonstrates that the systems biological approach can be useful for identifying novel therapeutic targets,” says Cho. The researchers are now expanding its breast cancer network model to include all breast cancer subtypes. Their ultimate aim is to identify more drug targets and to understand the mechanisms that could drive drug-resistant cells to turn into drug-sensitive ones. This work was supported by the National Research Foundation of Korea, the Ministry of Science and ICT, Electronics and Telecommunications Research Institute, and the KAIST Grand Challenge 30 Project. -Publication Sea R. Choi, Chae Young Hwang, Jonghoon Lee, and Kwang-Hyun Cho, “Network Analysis Identifies Regulators of Basal-like Breast Cancer Reprogramming and Endocrine TherapyVulnerability,” Cancer Research, November 30. (doi:10.1158/0008-5472.CAN-21-0621) -ProfileProfessor Kwang-Hyun ChoLaboratory for Systems Biology and Bio-Inspired EngineeringDepartment of Bio and Brain EngineeringKAIST
Simulations Open a New Way to Reverse Cell Aging
Turning off a newly identified enzyme could reverse a natural aging process in cells. Research findings by a KAIST team provide insight into the complex mechanism of cellular senescence and present a potential therapeutic strategy for reducing age-related diseases associated with the accumulation of senescent cells. Simulations that model molecular interactions have identified an enzyme that could be targeted to reverse a natural aging process called cellular senescence. The findings were validated with laboratory experiments on skin cells and skin equivalent tissues, and published in the Proceedings of the National Academy of Sciences (PNAS). “Our research opens the door for a new generation that perceives aging as a reversible biological phenomenon,” says Professor Kwang-Hyun Cho of the Department of Bio and Brain engineering at the Korea Advanced Institute of Science and Technology (KAIST), who led the research with colleagues from KAIST and Amorepacific Corporation in Korea. Cells respond to a variety of factors, such as oxidative stress, DNA damage, and shortening of the telomeres capping the ends of chromosomes, by entering a stable and persistent exit from the cell cycle. This process, called cellular senescence, is important, as it prevents damaged cells from proliferating and turning into cancer cells. But it is also a natural process that contributes to aging and age-related diseases. Recent research has shown that cellular senescence can be reversed. But the laboratory approaches used thus far also impair tissue regeneration or have the potential to trigger malignant transformations. Professor Cho and his colleagues used an innovative strategy to identify molecules that could be targeted for reversing cellular senescence. The team pooled together information from the literature and databases about the molecular processes involved in cellular senescence. To this, they added results from their own research on the molecular processes involved in the proliferation, quiescence (a non-dividing cell that can re-enter the cell cycle) and senescence of skin fibroblasts, a cell type well known for repairing wounds. Using algorithms, they developed a model that simulates the interactions between these molecules. Their analyses allowed them to predict which molecules could be targeted to reverse cell senescence. They then investigated one of the molecules, an enzyme called PDK1, in incubated senescent skin fibroblasts and three-dimensional skin equivalent tissue models. They found that blocking PDK1 led to the inhibition of two downstream signalling molecules, which in turn restored the cells’ ability to enter back into the cell cycle. Notably, the cells retained their capacity to regenerate wounded skin without proliferating in a way that could lead to malignant transformation. The scientists recommend investigations are next done in organs and organisms to determine the full effect of PDK1 inhibition. Since the gene that codes for PDK1 is overexpressed in some cancers, the scientists expect that inhibiting it will have both anti-aging and anti-cancer effects. -Profile Professor Kwang-Hyun Cho Laboratory for Systems Biology and Bio-Inspired Engineering http://sbie.kaist.ac.kr Department of Bio and Brain Engineering KAIST
Cancer cell reversion may offer a new approach to colorectal cancer treatment
A novel approach to reverse the progression of healthy cells to malignant ones may offer a more effective way to eradicate colorectal cancer cells with far fewer side effects, according to a team of researchers based in South Korea. Colorectal cancer, or cancer of the colon, is the third most common cancer in men and the second most common in women worldwide. South Korea has the second highest incident rate of colorectal cancer in the world, topped only by Hungary, according to the World Cancer Research Fund. Their results were published as a featured cover article on January 2 in Molecular Cancer Research, a journal of the American Association for Cancer Research. Led by Kwang-Hyun Cho, a professor and associate vice president of research at KAIST , the researchers used a computational framework to analyze healthy colon cells and colorectal cancer cells. They found that some master regulator proteins involved in cellular replication helped healthy colon cells mature, or differentiate into their specific cell type, and remain healthy. One particular protein, called SETDB1, suppressed the helpful proteins, forcing new cells to remain in a state of immaturity with the potential to become cancerous. “This suggests that differentiated cells have an inherent resistance mechanism against malignant transformation and indicates that cellular reprogramming is indispensable for malignancy,” said Cho. “We speculated that malignant properties might be eradicated if the tissue-specific gene expression is reinstated — if we repress SETDB1 and allow the colon cells to mature and differentiate as they would normally.” Image credit: Kwang-Hyun Cho, KAIST Image restriction: News organizations may use or redistribute this image, with proper attribution, as part of news coverage of this paper only. Using human-derived cells, Cho and his team targeted the tissue-specific gene expression programs identified in their computational analysis. These are the blueprints for the proteins that eventually help immature cells differentiate into tissue-specific cell types, such as colon cells. When a person has a genetic mutation, or has exposure to certain environmental factors, this process can go awry, leading to an overexpression of unhelpful proteins, such as SEDTB1. The researchers specifically reduced the amount of SEDTB1 in these tissue-specific gene expression programs, which allowed the cells to mature and fully differentiate into colon cells. “Our experiment also shows that SETDB1 depletion combined with cytotoxic drugs might be potentially beneficial to anticancer treatment,” Cho said. Cytotoxic drugs are often used for cancer treatment because the type of medicine contains chemicals that are toxic to cancer cells which can prevent them from replicating or growing. He noted that this combination could be more effective in treating cancer by transforming the cancer cell state into a less malignant or resistant state. He eventually pursues a cancer reversion therapy alone instead of conventional cytotoxic drug therapy since the cancer reversion therapy can provide a much less painful experience for patients with cancer who often have severe side effects from treatments intended to kill off cancerous cells, such as chemotherapy. The researchers plan to continue studying how to return cancer cells to healthier states, with the ultimate goal of translating their work to therapeutic treatment for patients with colorectal cancer. “I think our study of cancer reversion would eventually change the current medical practice of treating cancer toward the direction of keeping the patient’s quality of life while minimizing the side effects of current anti-cancer therapies,” Cho said. ### This work was funded by KAIST and the National Research Foundation of Korea grants funded by the Korean government, the Ministry of Science and Information and Communication Technology. Other authors include Soobeom Lee, Chae Young Hwang and Dongsan Kim, all of whom are affiliated with the Laboratory for Systems Biology and Bio-Inspired Engineering in the Department of Bio and Brain Engineering at KAIST; Chansu Lee and Sung Noh Hong, both with the Department of Medicine, and Seok-Hyung Kim of the Department of Pathology in the Samsung Medical Center at the Sungkyunkwan University School of Medicine. -Profile Professor Kwang-Hyun Cho firstname.lastname@example.org http://sbie.kaist.ac.kr/ Department of Bio and Brain Engineering KAIST https://www.kaist.ac.kr
Professor Kwang-Hyun Cho Recognzied by "Scientist of the Month" Award
Professor Kwang-Hyun Cho of KAIST’s Department of Bio and Brain Engineering received the “Scientist of the Month” award in February 2015 from the Ministry of Science, ICT, and Future Planning of the Republic of Korea and the National Research Foundation of Korea. The award was in recognition of Professor Cho’s contribution to the advanced technique of controlling the death of cancer cells based on systems biology, a convergence research in information technology (IT) and biotechnology. Professor Cho has published around 140 articles in international journals, including 34 papers in renowned science journals such as Nature, Science, and Cell in the past three years. His work also includes systems biology textbooks and many entries in international academic encyclopaedia. His field, systems biology, is a new biological research paradigm that identifies and controls the fundamental principles of organisms on a systems level. A well-known tumour suppressor protein, p53, is known to suppress abnormal cell growth and promote apoptosis of can cells, and thus was a focus of research by many scientists, but its effect has been insignificant and brought many side effects. This was due to the complex function of p53 that controls various positive and negative feedbacks. Therefore, there was a limit to understanding the protein with the existing biological approach. However, Professor Cho found the kinetic change and function of p53 via a systems biology approach. By applying IT technology to complex biological networks, he also identified the response to stress and the survival and death signal transduction pathways of cardiomyocytes and developed new control methods for cancer cells. Professor Cho said, “This award served as a momentum to turn over a new leaf.” He added, “I hope convergence research such as my field will bring more innovative ideas on the boundaries of academia.”
Prof. Cho Elected Editor-in-Chief of Systems Biology
Prof. Kwang-Hyun Cho of Department of Bio and Brain Engineering at KAIST has been recently elected editor-in-chief of the Systems Biology, an international journal published by the London-based Institution of Engineering and Technology (IET), the university authorities said on Wednesday (Sept. 23) By the year 2012, Cho will oversee the editorial process of the journal covering intra- and inter-cellular dynamics, using systems- and signal-oriented approaches. IET, one of the world"s leading professional societies for the engineering and technology community, has a worldwide membership of more than 150,000. Prof. Cho"s research interests cover the areas of systems science with bio-medical applications including systems biology and bio-inspired engineering based on molecular systems biology. He is currently an editorial board member of Systems and Synthetic Biology (Springer, Netherlands, from 2006), BMC Systems Biology (BMC, London, U.K., from 2007), Gene Regulation and Systems Biology (Libertas Academica, New Zealand, from 2007), and Bulletin of Mathematical Biology (Springer, New York, from 2008), and an editorial advisory board member of Molecular BioSystems (The Royal Society of Chemistry, U.K.).
Prof. Cho Appointed Editor-in-Chief of Systems Biology Encyclopedia
Prof. Kwang-Hyun Cho of the Department of Bio and Brain Engineering, KAIST, has been appointed as the editor-in-chief of the Encyclopedia of Systems Biology which is currently in development by Springer, a New York-based publishing company, university authorities said on Monday (July 6). Prof. Cho will share the position with three other eminent scholars from Britain, Germany and the United States. Cho will be responsible for selecting editorial members for each section of the Encyclopedia and overseeing the overall editorial process. The Encyclopedia of Systems Biology is a multi-volume reference compilation of the research outcomes in the field of systems biology all over the world. The ESB will consist of alphabetically ordered description of systems biology concepts and is envisaged to ultimately comprise 6-12 volumes. Publication of the Encyclopedia is scheduled for 2011.
Prof. Cho Identifies Dynamics of Signal Transportation System in Control of Cell Proliferation
KAIST, Jan. 22, 2009 -- A research team led by Prof. Kwang-Hyun Cho of the Department of Bio and Brain Engineering, KAIST, has identified a hidden mechanism of the dynamic behavior of signal transportation system involved in the control of cell proliferation, university authorities said. The finding is expected to provide a clue to appropriately controlling the pathway of ERK protein which is known to play a significant role in causing and spreading cancer. The research was featured as the cover paper of the latest online edition of the Journal of Cell Science. The Ras-Raf-MEK-ERK pathway (or ERK pathway) is an important signal transduction system involved in the control of cell proliferation, survival and differentiation. However, the dynamic regulation of the pathway by positive- and negative-feedback mechanism, in particular the functional role of Raf kinase inhibitor protein (RKIP) are still incompletely understood. RKIP is a physiological endogenous inhibitor of MEK phosphorylation by Raf kinases, but also participates in a positive-feedback loop in which ERK can inactivate RKIP. "We attempted to unearth the hidden dynamics of these feedback mechanisms and to identify the functional role of RKIP through combined efforts of biochemical experiments and computer simulations based on an experimentally validated mechanical model," Prof. Cho was quoted as saying.
KAIST Professor Named International Research Grant Reviewer
Prof. Kwang-Hyun Cho of the Department of Bio and Brain Engineering, KAIST, was appointed as a research grant review committee member of the international Human Frontier Science Program (HFSP) for 2008-2009, university authorities reported. The HFSP is a funding agency that supports international collaboration in interdisciplinary, basic research in the life sciences. It was initiated in 1989 by G7 countries as the sole funding program for international researches in neuroscience and molecular biology. The HFSP now has a membership of 35 countries and Korea joined the program in 2004. Prof. Cho will be responsible for reviewing grant applications in the field of systems biology. Prof. Cho received B.S., M.S. and Ph.D. degrees in electrical engineering from KAIST in 1993, 1995, and 1998, respectively. He has been working as a director of the KAIST Institute for the BioCentury and KAIST"s Laboratory for Systems Biology and Bio-Inspired Engineering. He has been serving on editorial advisory boards of various international science journals, including Systems and Synthetic Biology (Springer, Netherlands, from 2006), BMC Systems Biology (BMC, London, U.K., from 2007) and Gene Regulation and Systems Biology (Libertas Academica, New Zealand, from 2007). He is a senior member of the Engineering in Medicine and Biology Society (EMBS) affiliated with the Institute of Electronics and Electrical Engineers (IEEE). His research interests cover the areas of systems science with bio-medical applications, especially systems biology and bio-inspired engineering based on molecular systems biology.
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