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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
Identification of How Chemotherapy Drug Works Could Deliver Personalized Cancer Treatment
The chemotherapy drug decitabine is commonly used to treat patients with blood cancers, but its response rate is somewhat low. Researchers have now identified why this is the case, opening the door to more personalized cancer therapies for those with these types of cancers, and perhaps further afield. Researchers have identified the genetic and molecular mechanisms within cells that make the chemotherapy drug decitabine—used to treat patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) —work for some patients but not others. The findings should assist clinicians in developing more patient-specific treatment strategies. The findings were published in the Proceedings of the National Academies of Science on March 30. The chemotherapy drug decitabine, also known by its brand name Dacogen, works by modifying our DNA that in turn switches on genes that stop the cancer cells from growing and replicating. However, decitabine’s response rate is somewhat low (showing improvement in just 30-35% of patients), which leaves something of a mystery as to why it works well for some patients but not for others. To find out why this happens, researchers from the KAIST investigated the molecular mediators that are involved with regulating the effects of the drug. Decitabine works to activate the production of endogenous retroviruses (ERVs), which in turn induces an immune response. ERVs are viruses that long ago inserted dormant copies of themselves into the human genome. Decitabine in essence, ‘reactivates’ these viral elements and produces double-stranded RNAs (dsRNAs) that the immune system views as a foreign body. “However, the mechanisms involved in this process, in particular how production and transport of these ERV dsRNAs were regulated within the cell were understudied,” said corresponding author Yoosik Kim, professor in the Department of Chemical and Biomolecular Engineering at KAIST. “So to explain why decitabine works in some patients but not others, we investigated what these molecular mechanisms were,” added Kim. To do so, the researchers used image-based RNA interference (RNAi) screening. This is a relatively new technique in which specific sequences within a genome are knocked out of action or “downregulated.” Large-scale screening, which can be performed in cultured cells or within live organisms, works to investigate the function of different genes. The KAIST researchers collaborated with the Institut Pasteur Korea to analyze the effect of downregulating genes that recognize ERV dsRNAs and could be involved in the cellular response to decitabine. From these initial screening results, they performed an even more detailed downregulation screening analysis. Through the screening, they were able to identify two particular gene sequences involved in the production of an RNA-binding protein called Staufen1 and the production of a strand of RNA that does not in turn produce any proteins called TINCR that play a key regulatory role in response to the drug. Staufen1 binds directly to dsRNAs and stabilizes them in concert with the TINCR. If a patient is not producing sufficient Staufen1 and TINCR, then the dsRNA viral mimics quickly degrade before the immune system can spot them. And, crucially for cancer therapy, this means that patients with lower expression (activation) of these sequences will show inferior response to decitabine. Indeed, the researchers confirmed that MDS/AML patients with low Staufen1 and TINCR expression did not benefit from decitabine therapy. “We can now isolate patients who will not benefit from the therapy and direct them to a different type of therapy,” said first author Yongsuk Ku. “This serves as an important step toward developing a patient-specific treatment cancer strategy.” As the researchers used patient samples taken from bone marrow, the next step will be to try to develop a testing method that can identify the problem from just blood samples, which are much easier to acquire from patients. The team plans to investigate if the analysis can be extended to patients with solid tumors in addition to those with blood cancers. -Profile Professor Yoosik Kim https://qcbio.kaist.ac.kr/ Department of Chemical and Biomolecular Engineering KAIST -Publication Noncanonical immune response to the inhibition of DNA methylation by Staufen1 via stabilization of endogenous retrovirus RNAs, PNAS
What Fuels a “Domino Effect” in Cancer Drug Resistance?
KAIST researchers have identified mechanisms that relay prior acquired resistance to the first-line chemotherapy to the second-line targeted therapy, fueling a “domino effect” in cancer drug resistance. Their study featured in the February 7 edition of Science Advances suggests a new strategy for improving the second-line setting of cancer treatment for patients who showed resistance to anti-cancer drugs. Resistance to cancer drugs is often managed in the clinic by chemotherapy and targeted therapy. Unlike chemotherapy that works by repressing fast-proliferating cells, targeted therapy blocks a single oncogenic pathway to halt tumor growth. In many cases, targeted therapy is engaged as a maintenance therapy or employed in the second-line after front-line chemotherapy. A team of researchers led by Professor Yoosik Kim from the Department of Chemical and Biomolecular Engineering and the KAIST Institute for Health Science and Technology (KIHST) has discovered an unexpected resistance signature that occurs between chemotherapy and targeted therapy. The team further identified a set of integrated mechanisms that promotes this kind of sequential therapy resistance. “There have been multiple clinical accounts reflecting that targeted therapies tend to be least successful in patients who have exhausted all standard treatments,” said the first author of the paper Mark Borris D. Aldonza. He continued, “These accounts ignited our hypothesis that failed responses to some chemotherapies might speed up the evolution of resistance to other drugs, particularly those with specific targets.” Aldonza and his colleagues extracted large amounts of drug-resistance information from the open-source database the Genomics of Drug Sensitivity in Cancer (GDSC), which contains thousands of drug response data entries from various human cancer cell lines. Their big data analysis revealed that cancer cell lines resistant to chemotherapies classified as anti-mitotic drugs (AMDs), toxins that inhibit overacting cell division, are also resistant to a class of targeted therapies called epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). In all of the cancer types analyzed, more than 84 percent of those resistant to AMDs, representatively ‘paclitaxel’, were also resistant to at least nine EGFR-TKIs. In lung, pancreatic, and breast cancers where paclitaxel is often used as a first-line, standard-of-care regimen, greater than 92 percent showed resistance to EGFR-TKIs. Professor Kim said, “It is surprising to see that such collateral resistance can occur specifically between two chemically different classes of drugs.” To figure out how failed responses to paclitaxel leads to resistance to EGFR-TKIs, the team validated co-resistance signatures that they found in the database by generating and analyzing a subset of slow-doubling, paclitaxel-resistant cancer models called ‘persisters’. The results demonstrated that paclitaxel-resistant cancers remodel their stress response by first becoming more stem cell-like, evolving the ability to self-renew to adapt to more stressful conditions like drug exposures. More surprisingly, when the researchers characterized the metabolic state of the cells, EGFR-TKI persisters derived from paclitaxel-resistant cancer cells showed high dependencies to energy-producing processes such as glycolysis and glutaminolysis. “We found that, without an energy stimulus like glucose, these cells transform to becoming more senescent, a characteristic of cells that have arrested cell division. However, this senescence is controlled by stem cell factors, which the paclitaxel-resistant cancers use to escape from this arrested state given a favorable condition to re-grow,” said Aldonza. Professor Kim explained, “Before this research, there was no reason to expect that acquiring the cancer stem cell phenotype that dramatically leads to a cascade of changes in cellular states affecting metabolism and cell death is linked with drug-specific sequential resistance between two classes of therapies.” He added, “The expansion of our work to other working models of drug resistance in a much more clinically-relevant setting, perhaps in clinical trials, will take on increasing importance, as sequential treatment strategies will continue to be adapted to various forms of anti-cancer therapy regimens.” This study was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF-2016R1C1B2009886), and the KAIST Future Systems Healthcare Project (KAISTHEALTHCARE42) funded by the Korean Ministry of Science and ICT (MSIT). Undergraduate student Aldonza participated in this research project and presented the findings as the lead author as part of the Undergraduate Research Participation (URP) Program at KAIST. < Figure 1. Schematic overview of the study. > < Figure 2. Big data analysis revealing co-resistance signatures between classes of anti-cancer drugs. > Publication: Aldonza et al. (2020) Prior acquired resistance to paclitaxel relays diverse EGFR-targeted therapy persistence mechanisms. Science Advances, Vol. 6, No. 6, eaav7416. Available online at http://dx.doi.org/10.1126/sciadv.aav7416 Profile: Prof. Yoosik Kim, MA, PhD firstname.lastname@example.org https://qcbio.kaist.ac.kr/ Assistant Professor Bio Network Analysis Laboratory Department of Chemical and Biomolecular Engineering Korea Advanced Institute of Science and Technology (KAIST) http://kaist.ac.kr Daejeon, Republic of Korea Profile: Mark Borris D. Aldonza email@example.com Undergraduate Student Department of Biological Sciences Korea Advanced Institute of Science and Technology (KAIST) http://kaist.ac.kr Daejeon, Republic of Korea (END)
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
Researchers Describe a Mechanism Inducing Self-Killing of Cancer Cells
(Professor Kim (left) and lead author Lee) Researchers have described a new mechanism which induces the self-killing of cancer cells by perturbing ion homeostasis. A research team from the Department of Biochemical Engineering has developed helical polypeptide potassium ionophores that lead to the onset of programmed cell death. The ionophores increase the active oxygen concentration to stress endoplasmic reticulum to the point of cellular death. The electrochemical gradient between extracellular and intracellular conditions plays an important role in cell growth and metabolism. When a cell’s ion homeostasis is disturbed, critical functions accelerating the activation of apoptosis are inhibited in the cell. Although ionophores have been intensively used as an ion homeostasis disturber, the mechanisms of cell death have been unclear and the bio-applicability has been limited. In the study featured at Advanced Science, the team presented an alpha helical peptide-based anticancer agent that is capable of transporting potassium ions with water solubility. The cationic, hydrophilic, and potassium ionic groups were combined at the end of the peptide side chain to provide both ion transport and hydrophilic properties. These peptide-based ionophores reduce the intracellular potassium concentration and at the same time increase the intracellular calcium concentration. Increased intracellular calcium concentrations produce intracellular reactive oxygen species, causing endoplasmic reticulum stress, and ultimately leading to apoptosis. Anticancer effects were evaluated using tumor-bearing mice to confirm the therapeutic effect, even in animal models. It was found that tumor growth was strongly inhibited by endoplasmic stress-mediated apoptosis. Lead author Dr. Dae-Yong Lee said, “A peptide-based ionophore is more effective than conventional chemotherapeutic agents because it induces apoptosis via elevated reactive oxygen species levels. Professor Yeu-Chun Kim said he expects this new mechanism to be widely used as a new chemotherapeutic strategy. This research was funded by the National Research Foundation.
Early Genome Catastrophes Can Cause Non-Smoking Lung Cancer
Some teenagers harbor catastrophic changes to their genomes that can lead to lung cancer later on in life, even if they never smoke (Professor Young Seok Ju at the Graduate School of Medical Science and Engineering) Catastrophic rearrangements in the genome occurring as early as childhood and adolescence can lead to the development of lung cancer in later years in non-smokers. This finding, published in Cell, helps explain how some non-smoking-related lung cancers develop. Researchers at KAIST, Seoul National University and their collaborators confirmed that gene fusions in non-smokers mostly occur early on, sometimes as early as childhood or adolescence, and on average about three decades before cancer is diagnosed. The study showed that these mutant lung cells, harboring oncogenic seeds, remain dormant for several decades until a number of further mutations accumulate sufficiently for progression into cancer. This is the first study to reveal the landscape of genome structural variations in lung adenocarcinoma. Lung cancer is the leading cause of cancer-related deaths worldwide, and lung adenocarcinoma is its most common type. Most lung adenocarcinomas are associated with chronic smoking, but about a fourth develop in non-smokers. Precisely what happens in non-smokers for this cancer to develop is not clearly understood. Researchers analyzed the genomes of 138 lung adenocarcinoma patients, including smokers and non-smokers, with whole-genome sequencing technologies. They explored DNA damage that induced neoplastic transformation. Lung adenocarcinomas that originated from chronic smoking, referred to as signature 4-high (S4-high) cancers in the study, showed several distinguishing features compared to smoking-unrelated cancers (S4-low). People in the S4-high group were largely older, men and had more frequent mutations in a cancer-related gene called KRAS. Cancer genomes in the S4-high group were hypermutated with simple mutational classes, such as the substitution, insertion, or deletion of a single base, the building block of DNA. But the story was very different in the S4-low group. Generally, mutational profiles in this group were much more silent than the S4-high group. However, all cancer-related gene fusions, which are abnormally activated from the merging of two originally separate genes, were exclusively observed in the S4-low group. The patterns of genomic structural changes underlying gene fusions suggest that about three in four cases of gene fusions emerged from a single cellular crisis causing massive genomic fragmentation and subsequent imprecise repair in normal lung epithelium. Most strikingly, these major genomic rearrangements, which led to the development of lung adenocarcinoma, are very likely to be acquired decades before cancer diagnosis. The researchers used genomic archaeology techniques to trace the timing of when the catastrophes took place. Researchers started this study seven years ago when they discovered the expression of the KIF5B-RET gene fusion in lung adenocarcinoma for the first time. Professor Young-Seok Ju, co-lead author from the Graduate School of Medical Science and Engineering at KAIST says, “It is remarkable that oncogenesis can begin by a massive shattering of chromosomes early in life. Our study immediately raises a new question: What induces the mutational catastrophe in our normal lung epithelium.” Professor Young Tae Kim, co-lead author from Seoul National University says, “We hope this work will help us get one step closer to precision medicine for lung cancer patients.” The research team plans to further focus on the molecular mechanisms that stimulate complex rearrangements in the body, through screening the genomic structures of fusion genes in other cancer types. This study was supported by the National Research Foundation of Korea (NRF), Korea Health Industry Development Institute (KHIDI), Suh Kyungbae Foundation, the College of Medicine Research Foundations at Seoul National University and others. Figure. (Smoking-unrelated oncogenesis of lung cancers by gene fusions) Publication. Jake June-Koo Lee, Seongyeol Park et al., Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma Cell 177, June 13 2019, online publication ahead of print at May 30, 2019 https://doi.org/10.1016/j.cell.2019.05.013 Profile: Prof Young Seok Ju, MD, PhD email@example.com http://julab.kaist.ac.kr Associate Professor Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST) Daejeon 34141, Korea Profile: Prof Young Tae Kim, MD, PhD firstname.lastname@example.org Professor Seoul National University Cancer Research Institute Department of Thoracic and Cardiovascular Surgery Seoul National University Hospital Seoul 03080, Korea
5 Biomarkers for Overcoming Colorectal Cancer Drug Resistance Identified
< Professor Kwang-Hyun Cho's Team > KAIST researchers have identified five biomarkers that will help them address resistance to cancer-targeting therapeutics. This new treatment strategy will bring us one step closer to precision medicine for patients who showed resistance. Colorectal cancer is one of the most common types of cancer worldwide. The number of patients has surpassed 1 million, and its five-year survival rate significantly drops to about 20 percent when metastasized. In Korea, the surge of colorectal cancer has been the highest in the last 10 years due to increasing Westernized dietary patterns and obesity. It is expected that the number and mortality rates of colorectal cancer patients will increase sharply as the nation is rapidly facing an increase in its aging population. Recently, anticancer agents targeting only specific molecules of colon cancer cells have been developed. Unlike conventional anticancer medications, these selectively treat only specific target factors, so they can significantly reduce some of the side-effects of anticancer therapy while enhancing drug efficacy. Cetuximab is the most well-known FDA approved anticancer medication. It is a biomarker that predicts drug reactivity and utilizes the presence of the ‘KRAS’ gene mutation. Cetuximab is prescribed to patients who don’t carry the KRAS gene mutation. However, even in patients without the KRAS gene mutation, the response rate of Cetuximab is only about fifty percent, and there is also resistance to drugs after targeted chemotherapy. Compared with conventional chemotherapy alone, the life expectancy only lasts five months on average. In research featured in the FEBS Journal as the cover paper for the April 7 edition, the KAIST research team led by Professor Kwang-Hyun Cho at the Department of Bio and Brain Engineering presented five additional biomarkers that could increase Cetuximab responsiveness using systems biology approach that combines genomic data analysis, mathematical modeling, and cell experiments. The experimental inhibition of newly discovered biomarkers DUSP4, ETV5, GNB5, NT5E, and PHLDA1 in colorectal cancer cells has been shown to overcome Cetuximab resistance in KRAS-normal genes. The research team confirmed that when suppressing GNB5, one of the new biomarkers, it was shown to overcome resistance to Cetuximab regardless of having a mutation in the KRAS gene. Professor Cho said, “There has not been an example of colorectal cancer treatment involving regulation of the GNB5 gene.” He continued, “Identifying the principle of drug resistance in cancer cells through systems biology and discovering new biomarkers that could be a new molecular target to overcome drug resistance suggest real potential to actualize precision medicine.” This study was supported by the National Research Foundation of Korea (NRF) and funded by the Ministry of Science and ICT (2017R1A2A1A17069642 and 2015M3A9A7067220). Image 1. The cover of FEBS Journal for April 2019
Autophagy in Dendritic Cells Helps Anticancer Activity
Autophagy contributes to the homeostasis of a cell and recently another function of autophagy has been reported. A KAIST research team found that the autophagy of dendritic cells supports T-cell anticancer activity. Autophagy is a process of maintaining cell homeostasis by removing cellular waste and damaged cellular organelles; nevertheless, its role in the presentation of phagocytized tumor-associated antigens remains vague. Meanwhile, dendritic cells are the ones that recognize pathogens or cancer antigens, and induce immune responses in T cells. When cancer cells are killed by radiation or an anticancer drug, dendritic cells absorb and remove them and present antigens on their surface to transfer them to T-cells. Professor Heung Kyu Lee from the Graduate School of Medical Science and Engineering and his team found that the autophagy of dendritic cells plays a key role in T-cell activation and they proposed the principles of enhancing anti-cancer effects. Their experiments showed that T-cell activation of dendritic cells as well as anticancer immune response dropped when there is a deficiency of Atg5 (autophagy-related) in dendritic cells. Interestingly, Atg5-deficient dendritic cells significantly elevated receptor CD36 on the surface of the cells, which increased the phagocytosis of apoptotic tumor cells yet restricted the activation of T-cells. At this time, when introducing antibodies into the system in order to block the receptor CD36, the anti-tumor T-cell response increased substantially while tumor growth declined. Professor Lee said, “This study allowed us to explore the role of autophagy in the anti-cancer immune response of T-cells. We look forward to developing targeted anti-cancer therapies using the receptor CD36.” This research was published in Autophagy (10.1080/15548627.2019.1596493) on March 22, 2019. Figure 1.Mechanism of autophagy in dendritic cells Figure 2. A role of autophagy in dendritic cells
'K-FLEX' Makes a Splash as a Flexible Endoscopic Surgical Robot
( Robot arms perform an incision during an ex-vivo test on a porcine gallbladder.) K-FLEX, a flexible endoscopic surgical robot developed by the KAIST Future Medical Robotics Research Center, opens a new chapter for minimally invasive robot-assisted surgery with its precision control of 3.7 mm diameter robotic arms. The two arms, placing at the end of flexible endoscopes, highlight impeccable precision control and robust mini-joint design technologies. While cruising through the complicated inner body pliably, it carries out procedures on the spot with its robotic arms. The research team under Professor Dong-Soo Kwon recently tested the device in-vivo, conducting a complicated endoscopic procedure dissecting a porcine gallbladder in collaboration with Professor Dae-Kyung Son of the National Cancer Center. The arms successfully manipulated the tissue safely. During the test, K-FLEX, inserted through an incision in the navel, snaked through the narrow passages of the complicated inner organs. When reaching the desired spot, one of the robot arms pushed aside and held up the nearby tissue to secure proper vision and space for the procedure. Meanwhile, a cautery needle mounted at the tip of the other hand removed the lesion tissue on the gallbladder. The tiny camera installed at the front of the robot arms relayed the internal conditions. The full procedure was able to be monitored from the master console. The two arms are placed onto 4.2 mm internal channels of an endoscope which is 17 mm in diameter. The arms can be deployable forward and backward and are extendable up to 7 cm for performing procedures. K-FLEX is made of domestically produced components, except for the endoscopic module. It will expand new medical robotics research while offering novel therapeutic capabilities for endoscopes. Flexible endoscopes are very promising for surgical applications because they can treat areas thought to be difficult to reach, such as the posterior side of an organ. Current rigid-type laparoscopic tools could not reach a lesion if it occurs in such serpentine and complicated areas. However, this flexible endoscopic surgery robot will bypass obstacles to reach the troubled area. The ability to seamlessly integrate effective actuation into millimeter-scale deployable mechanisms fits well with minimally invasive surgical procedures. This flexible endoscopic surgery robot, only half the size of current laparoscopic surgical robots, is deployable into natural orifices such as the mouth, anus, and vagina without requiring external incisions. Laparoscopic devices and robots require at least three to four external incisions to insert the devices; however, the applicability of internal incisions reduces the possibility of complications arousing from excessive bleeding and bacterial infections. Despite these advantages, it has remained challenging to manipulate the robotic arms of flexible endoscopes with integrated grabbing force, flexibility, and multiple degrees of freedom for clinical environments. The team focused on smaller but smarter devices. Dr. Min-Ho Hwang, a principal researcher of K-FLEX, said that developing tiny robots that are able to generate the necessary forces without compromising safety was the challenge. They created a robust but smaller-joint technology that can exert a relatively greater force even into millimeter scale. Professor Kwon said, “K-FLEX is the first flexible endoscopic surgery robot in Korea. We already confirmed the clinical adaptation through ex vivo tests and will see complete commercialization in two to three years.” The team believes K-FLEX will be very effective for surgery on incipient cancer cells in the stomach, colon, and thyroid. Professor Kwon and his eight researchers recently established a tech start-up called EasyEndo Surgical Inc. with these core technologies. In June, K-FLEX won the ‘Best Application Award’ and the ‘Overall Winner’ at the Surgical Robot Challenge 2018 held at Imperial College London. The Korea Research Foundation funded the research on K-FLEX. (The team conducts a procedure using K-FLEX, flexible endoscopic surgical robot.)
Professor Hee-Sung Park Named Scientist of May
(Professor Hee-Sung Park) Professor Hee-Sung Park from the Department of Chemistry was named ‘Scientist of May’ sponsored by the Ministry of Science and ICT and the National Research Foundation of Korea. Professor Park was honored in recognition of his developing a tool to engineer designer proteins via diverse chemical modifications. This approach provides a novel platform for investigating numerous diseases such as cancer and dementia. His research focuses on the production of synthetic proteins and the generation of diverse protein functions as well as the designing and engineering of new translation machinery for genetic code expansion, and the application of synthetic biology techniques for basic cell biology and applied medical science. Post-translational modifications (PTMs) are constantly taking place during or after protein biosynthesis. PTMs play a vital role in expanding protein functional diversity and, as a result, critically affect numerous biological processes. Abnormal PTMs have been known to trigger various diseases including cancer and dementia. Therefore, this technology enables proteins to reproduce with specific modifications at selected residues and will significantly help establish experimental strategies to investigate fundamental biological mechanisms including the development of targeted cancer therapies. Professor Park also received 10 million KRW in prize money.
Professor Ju, to Receive Grants from HFSP
(Professor Young Seok Ju) Professor Young Seok Ju from the Graduate School of Medical Science and Engineering was selected as a young investigator to receive research funds from the Human Frontiers Science Program. The Human Frontiers Science Program (HFSP) was founded in 1989 with members of the G7 and European Union to stimulate innovative research in the field of life sciences. Professor Ju placed third out of the eight teams that were selected from 158 applicants representing 60 countries. He is now the fourth Korean to receive a research grant as a young investigator. Professor Jae Kyoung Kim from the Department of Mathematical Sciences also received this prize last year, hence KAIST has produced grant recipients for two consecutive years. Professor Ju is a medical doctor specializing in cancer genomics and computer biology. He has been studying somatic mutations and their functional consequences in human cancer in a bioinformatics way. He has published papers in international journals including Nature, Science, Genome Research, and Journal of Clinical Oncology. With a title ‘Tracing AID/APOBEC- and MSI-mediated hyper-mutagenesis in the clonal evolution of gastric cancer,’ Professor Ju will receive 1.05 million dollars for three years along with Professor Bon-Kyoung Koo from the Institute of Molecular Biotechnology at Austrian Academy of Sciences, and Sinppert Hugo from University Medical Center Utrecht. Professor Ju said, “As a young investigator, it is my great honor to receive this research fund from this organization. Through this internationally collaborative research, I will carry out groundbreaking research to understand the pathophysiology of cancers at a molecular level.”
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