Research
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Photoacoustic Imaging and Photothermal Cancer Therapy Using BR Nanoparticles
(Professor Sangyong Jon and PhD Candidate Dong Yun Lee)
Sangyong Jon, a professor in the Department of Biological Sciences at KAIST, and his team developed combined photoacoustic imaging and photothermal therapy for cancer by using Bilirubin (BR) nanoparticles.
The research team applied the properties of a bile pigment called BR, which exerts potent antioxidant and anti-inflammatory effects, to this research.
The team expects this research, which shows high biocompatibility as well as outstanding photoacoustic imaging and photothermal therapy, to be an appropriate system in the field of treatment for cancer.
In the past, the research team developed a PEGylated bilirubin-based nanoparticle system by combining water-insoluble BR with water-soluble Polyethylene Glycol (PEG).
This technology facilitated BR exerting antioxidants yet prevented them from being accumulated in the body. Its efficiency and safety was identified in an animal disease model, for conditions such as inflammatory bowel disease, islet cell transportation, and asthma.
Differing from previous research methods, this research applied the different physicochemical properties of BR to cancer treatment.
When the causative agent of jaundice, yellow BR, is exposed to a certain wavelength of blue light, the agent becomes a photonic nanomaterial as it responses to the light. This light-responsive nanomaterial can be used to cure jaundice because it allows for active excretion in infants.
Secondly, the team identified that BR is a major component of black pigment gallstones which can be often found in gall bladders or bile ducts under certain pathological conditions. The findings show that BR forms black pigment gallstones without the role of an intermediate or cation, such as calcium and copper. The research team combined cisplatin, a platinum metal-based anticancer drug, with BR so that BR nanoparticles changed the solution color from yellow to purple.
The team also examined the possibility of cisplatin-chelated BR nanoparticles as a probe for photoacoustic images. They found that considerable photoacoustic activity was shown when it was exposed to near infrared light. In fact, the photoacoustic signal was increased significantly in tumors of animals with colorectal cancer when the nanoparticles were administered to it intravenously. The team expects a more accurate diagnosis of tumors through this technology.
Moreover, the team assessed the photothermal effects of cisplatin-chelated BR nanoparticles. The research showed that the temperature of tumors increased by 25 degrees Celsius within five minutes when they were exposed to near infrared light, due to the photothermal effect. After two weeks, their size was reduced compared to that of other groups, and sometimes the tumors were even necrotized.
Professor Jon said, “Existing substances have a low biocompatibility and limitation for clinical therapy because they are artificially oriented; therefore, they might have toxicity. I am hoping that these cisplatin-chelated BR-based nanoparticles will provide a new platform for preclinical, translational research and clinical adaptation of the photoacoustic imaging and photothermal therapy.”
The paper (Dong Yun Lee as a first author) was published online in the renowned journal in the field of applied chemistry, Angewandte Chemi International Edition, on September 4. This research was sponsored by the National Research Foundation of Korea.
(Schematic diagram of the research)
(From left: Bilirubin nanoparticles, cisplatin-chelated Bilirubin nanoparticles)
2017.09.26 View 8814 -
Research Center for Smart Submerged Floating Tunnel Systems Opens
(Distinguished guests including President Shin (fourth from the right) and Director Lee (third from left) at the opening ceremony)
The Research Center for a Smart Submerged Floating Tunnel Systems was recently established at KAIST with the purpose of taking the lead in developing fundamental and applicable technology for submerged floating tunnels as well as fostering creative and talented people. Haeng-Ki Lee, a professor in the Department of Civil & Environmental Engineering at KAIST is heading the center.
KAIST held its opening ceremony on September 7, 2017 in the Applied Engineering Building located on the main campus.
Distinguished guests, including KAIST president Sung-Chul Shin, the President of the Korea Institute of Ocean Science and Technology Gi-Hoon Hong, the President of the Korean Society of Civil Engineering Young-Seok Park, and the Director in the Division of Engineering at the National Research Foundation of Korea Joong-Kon Park attended the ceremony.
The National Research Foundation of Korea provides Engineering Research Center (ERC) projects which find and foster groups with outstanding research performance in a field of engineering. The projects support these groups so that they can strengthen their global competitiveness while enhancing national competence in basic research.
The ‘Research Center for Smart Submerged Floating Tunnel Systems’ was selected as one of the ERC projects in 2017. For the next seven years, the research center will work to develop a submerged floating tunnel system resistant depths greater than 100 meters.
To achieve its goal, the center has defined crucial research topics including: i) a structural analysis program and integrated design technology specific for submerged floating tunnel systems, ii) high-durability marine construction materials and submerged construction integrated systems, and iii) safety and maintenance integrated technology for smart submerged floating tunnel systems.
The ‘Research Center for Smart Submerged Floating Tunnel Systems’ will devote itself to developing a variety of fundamental and applicable technology that will be leading global maritime construction. Moreover, it will concentrate on fostering professional research manpower in related areas.
The Director of the Center Lee said, “The center will cooperate with KAIST researchers who are experts in various fields, including structures, materials, construction, and maritime research. Based on this collaboration, the center will contribute to achieving autonomous technologies by developing fundamental and applicable technology related with submerged floating tunnel systems. It will also take the role of a leading global research hub in the field of submerged floating tunnels as well as construction technologies.”
2017.09.07 View 9307 -
Discovery of an Optimal Drug Combination: Overcoming Resistance to Targeted Drugs for Liver Cancer
A KAIST research team presented a novel method for improving medication treatment for liver cancer using Systems Biology, combining research from information technology and the life sciences. Professor Kwang-Hyun Cho in the Department of Bio and Brain Engineering at KAIST conducted the research in collaboration with Professor Jung-Hwan Yoon in the Department of Internal Medicine at Seoul National University Hospital. This research was published in Hepatology in September 2017 (available online from August 24, 2017).
Liver cancer is the fifth and seventh most common cancer found in men and women throughout the world, which places it second in the cause of cancer deaths. In particular, Korea has 28.4 deaths from liver cancer per 100,000 persons, the highest death rate among OECD countries and twice that of Japan.
Each year in Korea, 16,000 people get liver cancer on average, yet the five-year survival rate stands below 12%. According to the National Cancer Information Center, lung cancer (17,399) took the highest portion of cancer-related deaths, followed by liver cancer (11,311) based on last year data.
Liver cancer is known to carry the highest social cost in comparison to other cancers and it causes the highest fatality in earlier age groups (40s-50s). In that sense, it is necessary to develop a new treatment that mitigates side effects yet elevates the survival rate.
There are ways in which liver cancer can be cured, such as surgery, embolization, and medication treatments; however, the options become limited for curing progressive cancer, a stage in which surgical methods cannot be executed.
Among anticancer medications, Sorafenib, a drug known for enhancing the survival rate of cancer patients, is a unique drug allowed for use as a targeted anticancer medication for progressive liver cancer patients. Its sales reached more than ten billion KRW annually in Korea, but its efficacy works on only about 20% of the treated patients. Also, acquired resistance to Sorafenib is emerging. Additionally, the action mechanism and resistance mechanism of Sorafenib is only vaguely identified.Although Sorafenib only extends the survival rate of terminal cancer patients less than three months on average, it is widely being used because drugs developed by global pharmaceutical companies failed to outperform its effectiveness.
Professor Cho’s research team analyzed the expression changes of genes in cell lines in response to Sorafenib in order to identify the effect and the resistance mechanism of Sorafenib.
As a result, the team discovered the resistance mechanism of Sorafenib using Systems Biology analysis. By combining computer simulations and biological experiments, it was revealed that protein disulfide isomerase (PDI) plays a crucial role in the resistance mechanism of Sorafenib and that its efficacy can be improved significantly by blocking PDI.
The research team used mice in the experiment and discovered the synergic effect of PDI inhibition with Sorafenib for reducing liver cancer cells, known as hepatocellular carcinoma. Also, more PDIs are shown in tissue from patients who possess a resistance to Sorafenib. From these findings, the team could identify the possibility of its clinical applications. The team also confirmed these findings from clinical data through a retrospective cohort study.
“Molecules that play an important role in cell lines are mostly put under complex regulation. For this reason, the existing biological research has a fundamental limitations for discovering its underlying principles,” Professor Cho said. “This research is a representative case of overcoming this limitation of traditional life science research by using a Systems Biology approach, combining IT and life science. It suggests the possibility of developing a new method that overcomes drug resistance with a network analysis of the targeted drug action mechanism of cancer.”
The research was supported by the National Research Foundation of Korea (NRF) and funded by the Ministry of Science and ICT.
(Figure 1. Simulation results from cellular experiments using hepatocellular carcinoma)
(Figure 2. Network analysis and computer simulation by using the endoplasmic reticulum (ER) stress network)
(Figure 3. ER stress network model)
2017.08.30 View 11679 -
The Medici Effect: Highly Flexible, Wearable Displays Born in KAIST
(Ph.D. candidate Seungyeop Choi)
How do you feel when technology you saw in a movie is made into reality? Collaboration between the electrical engineering and textile industries has made TVs or smartphone screens displaying on clothing a reality.
A research team led by Professor Kyung Cheol Choi at the School of Electrical Engineering presented wearable displays for various applications including fashion, IT, and healthcare. Integrating OLED (organic light-emitting diode) into fabrics, the team developed the most highly flexible and reliable technology for wearable displays in the world.
Recently, information displays have become increasingly important as they construct the external part of smart devices for the next generation. As world trends are focusing on the Internet of Things (IoTs) and wearable technology, the team drew a lot of attention by making great progress towards commercializing clothing-shaped ‘wearable displays’.
The research for realizing displays on clothing gained considerable attention from academia as well as industry when research on luminescence formed in fabrics was introduced in 2011; however, there was no technology for commercializing it due to its surface roughness and flexibility.
Because of this technical limitation, clothing-shaped wearable displays were thought to be unreachable technology. However, the KAIST team recently succeeded in developing the world’s most highly efficient, light-emitting clothes that can be commercialized.
The research team used two different approaches, fabric-type and fiber-type, in order to realize clothing-shaped wearable displays. In 2015, the team successfully laminated a thin planarization sheet thermally onto fabric to form a surface that is compatible with the OLEDs approximately 200 hundred nanometers thick. Also, the team reported their research outcomes on enhancing the reliability of operating fiber-based OLEDs. In 2016, the team introduced a dip-coating method, capable of uniformly depositing layers, to develop polymer light-emitting diodes, which show high luminance even on thin fabric.
Based on the research performance in 2015 and 2016, Ph.D. candidate Seungyeop Choi took the lead in the research team and succeeded in realizing fabric-based OLEDs, showing high luminance and efficiency while maintaining the flexibility of the fabric.
The long-term reliability of this wearable device that has the world’s best electrical and optical characteristics was verified through their self-developed, organic and inorganic encapsulation technology. According to the team, their wearable device facilitates the operation of OLEDs even at a bending radius of 2mm.
According to Choi, “Having wavy structures and empty spaces, fiber plays a significant role in lowering the mechanical stress on the OLEDs.”
“Screen displayed on our daily clothing is no longer a future technology,” said Professor Choi. “Light-emitting clothes will have considerable influence on not only the e-textile industry but also the automobile and healthcare industries.”
Moreover, the research team remarked, “It means a lot to realize clothing-shaped OLEDs that have the world’s best luminance and efficiency. It is the most flexible fabric-based light-emitting device among those reported. Moreover, noting that this research carried out an in-depth analysis of the mechanical characteristics of the clothing-spared, light-emitting device, the research performance will become a guideline for developing the fabric-based electronics industry.”
This research was funded by the Ministry of Trade, Industry and Energy and collaborated with KOLON Glotech, INC. The research performance was published in Scientific Reports in July.
(OLEDs operating in fabrics)
(Current-voltage-luminance and efficiency of the highly flexible, fabric-based OLEDs;Image of OLEDs after repetitive bending tests;Verification of flexibility through mechanical simulation)
2017.08.24 View 15084 -
Material-Independent Nanocoating Antimicrobial Spray Significantly Extends the Shelf Life of Produce
The edible coating on produce has drawn a great deal of attention in the food and agricultural industry. It could not only prolong postharvest shelf life of produce against external changes in the environment but also provide additional nutrients to be useful for human health. However, most versions of the coating have had intrinsic limitations in their practical application. First, highly specific interactions between coating materials and target surfaces are required for a stable and durable coating. Even further, the coating of bulk substrates, such as fruits, is time consuming or is not achievable in the conventional solution-based coating. In this respect, material-independent and rapid coating strategies are highly demanded.
The research team led by Professor Insung Choi of the Department of Chemistry developed a sprayable nanocoating technique using plant-derived polyphenol that can be applied to any surface. This new nanocoating process can be completed in seconds to form nanometer-thick films, allowing for the coating of commodity goods, such as shoe insoles and fruits, in a controlled fashion. For example, spray-coated mandarin oranges and strawberries show significantly-prolonged postharvest shelf life, suggesting the practical potential in edible coatings of perishable produce.
The technology has been patented and is currently being commercialized for widespread use as a means of preserving produce. The research results have recently been published in Scientific Reports on Aug 1.
Polyphenols, a metabolite of photosynthesis, possess several hydroxyl groups and are found in a large number of plants showing excellent antioxidant properties. They have been widely used as a nontoxic food additive and are known to exhibit antibacterial, as well as potential anti-carcinogenic capabilities. Polyphenols can also be used with iron ions, which are naturally found in the body, to form an adhesive complex, which has been used in leather tanning, ink, etc.
The research team combined these chemical properties of polyphenol-iron complexes with spray techniques to develop their nanocoating technology. Compared to conventional immersion coating methods, which dip substrates in specialized coating solutions, this spray technique can coat the select areas more quickly. The spray also prevents cross contamination, which is a big concern for immersion methods. The research team has showcased the spray’s ability to coat a variety of different materials, including metals, plastics, glass, as well as textile fabrics. The polyphenol complex has been used to form antifogging films on corrective lenses, as well as antifungal treatments for shoe soles, demonstrating the versatility of their technique.
Furthermore, the spray has been used to coat produce with a naturally antibacterial, edible film. The coatings significantly improved the shelf life of tangerines and strawberries, preserving freshness beyond 28 days and 58 hours, respectively. (Uncoated fruit decomposed and became moldy under the same conditions). See the image below.
a –I, II: Uncoated and coated tangerines incubated for 14 and 28 days in daily-life settings
b –I: Uncoated and coated strawberries incubated for 58 hours in daily-life settings
b –II: Statistical investigation of the resulting edibility.
Professor Choi said, “Nanocoating technologies are still in their infancy, but they have untapped potential for exciting applications. As we have shown, nanocoatings can be easily adapted for several different uses, and the creative combination of existing nanomaterials and coating methods can synergize to unlock this potential.”
2017.08.10 View 9254 -
KAIST Researchers Receive Awards at the 13th Asian Congress on Biotechnology
(From left: Seon Young Park, Dr. So Young Choi, and Yoojin Choi)
Researchers in the laboratory of KAIST Distinguished Professor Sang Yup Lee from the Department of Chemical and Biomolecular Engineering swept awards at the 13th Asian Congress on Biotechnology held in Thailand last month. The conference awarded a total of eight prizes in the areas of best research and best poster presentation. This is an exceptional case in which members of one research team received almost half of the awards at an international conference.
Dr. So Young Choi received the Best Research Award, while Ph.D. candidates Yoojin Choi and Seon Young Park each received the Best Poster Presentation Award at the conference held in Khon Kaen, Thailand from July 23 to 27.
The Asian Congress on Biotechnology is an international conference in which scientists and industry experts in Asia and from around the world gather to present recent research findings in the field of biotechnology. At the conference, around 400 researchers in biotechnology from 25 countries, including Korea, gathered to present and discuss various research findings under the theme of “Bioinnovation and Bioeconomy.”
Distinguished Professor Sang Yup Lee attended the conference to give the opening plenary lecture on the topic of ‘Systems Strategies in Biotechnology.’ Professor Lee announced, “I have attended international conferences with students for the last 20 years, but this is the first in which my team received three awards at an international conference that only honors a total of eight awards, three for Best Research and five for Best Presentation.”
Dr. Choi presented research results on poly (lactate-co-glycolate) (PLGA) synthesis through a biological method using micro-organisms and received the Best Research Award. PLGA is a random copolymer of DL-lactic and glycolic acids and is a biopolymer widely used for biomedical applications. PLGA is biodegradable, biocompatible, and nontoxic, and thus has been approved by the US Food and Drug Administration (FDA) for its use in implants, drug delivery, and sutures.
Dr. Choi’s research was deemed to be innovative for synthesizing PLGA from glucose and xylose in cells through metabolic engineering of E.Coli. Dr. Choi received her Ph.D. under the supervision of Distinguished Professor Lee this February and is currently conducting post-doc research.
Ph.D. candidate Choi presented her research on the use of recombinant E.Coli for the biological synthesis of various nanoparticles and received the Best Poster Presentation award. Choi used recombinant E.Coli-expressing proteins and peptides that adsorb to heavy metals to biologically synthesize diverse metal nanoparticles such as single-nanoparticle including gold and silver, quantum dots, and magnetic nanoparticles for the first time. The synthesized nanoparticles can be used in the fields of bio-imaging, diagnosis, environment, and energy.
Ph.D. candidate Park, who also received the Best Poster Presentation award, synthesized and increased production of astanxanthin, a strong antioxidant found in nature, in E.Coli using metabolic engineering. Astanxanthin is a carotenoid pigment found in salmon and shrimp that widely used in health products and cosmetics.
2017.08.01 View 14359 -
KAIST to Host the 2017 AI World Cup in November
KAIST, the birthplace of the Robot World Cup in 1996, now presents a new technology matchup, the AI World Cup this November, which will be held at KAIST. The event is being organized by the Machine Intelligence and Robotics Multi-Sponsored Research and Education Platform (MIR-MSREP) of KAIST. The online, simulated AI soccer game, based on rolling updates, will be a draw for avid online gamers and tech-savvy university students from around the nation.
The tournament is comprised of three events: ▲A 5 on 5 AI soccer match to be played after self-learning using AI technology in an online simulation environment ▲Commentary in which online soccer videos are analyzed and commented on, and ▲Game reporters who will write articles on online soccer event results.
The participants will undergo a month-long online practice period in October and compete in preliminary matches from November 1 through 24. The top teams that scored the highest accumulated points will compete in the finals on December 1. In the finals, each team’s AI technology implementation method will be evaluated to select the final winning team. To ensure a successful event, KAIST will host a briefing session for participants on July 28.
Technological prowess and early exposure to AI accumulated at KAIST led to the launching of this tournament. Professor Jong-Hwan Kim, the chair of the Organizing Committee of the AI World Cup, hosted the first ever Robot World Cup back in 1996. His concept has now evolved into the emerging technology of AI and the members of the Organizing Committee encompass the professors from the various departments of electrical engineering, computing, industrial and systems engineering, aerospace engineering, civil and environmental engineering, and the graduate schools of Green Transportation, Cultural Technology, and Science and Technology Policy.
In particular, ongoing convergence research initiatives incorporating AI into a wide arrays of disciplines such as bio, nano, and IT, played a crucial role for making this AI World Cup happen. Professor Kim said, “The winner of this year’s competition will be awarded a certificate and a small gift. In 2018, we aim to expand the event to an international scale by allowing international teams.”
Any undergraduate or graduate student in Korea can apply to participate in the ‘AI World Cup 2017’. KAIST will host a public trial event during the ‘Open KAIST’ event period to be held November 2-3 to help participating students understand the event better. ‘Open KAIST’ allows the general public to personally visit and experience what goes on in engineering departments and laboratories on the KAIST main campus. It is hosted by the College of Engineering every two years and is the largest event hosted by KAIST.
To participate in the ‘AI World Cup 2017,’ teams consisting of Korean undergraduates or graduate students can fill out application forms and submit them by September 30 on http://mir.kaist.ac.kr .
2017.07.14 View 11264 -
Cooperative Tumor Cell Membrane-Targeted Phototherapy
A KAIST research team led by Professor Ji-Ho Park in the Bio and Brain Engineering Department at KAIST developed a technology for the effective treatment of cancer by delivering synthetic receptors throughout tumor tissue. The study, led by Ph.D. candidate Heegon Kim, was published online in Nature Communications on June 19.
Cancer targeted therapy generally refers to therapy targeting specific molecules that are involved in the growth and generation of cancer. The targeted delivery of therapeutics using targeting agents such as antibodies or nanomaterials has improved the precision and safety of cancer therapy.
However, the paucity and heterogeneity of identified molecular targets within tumors have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes.
To solve this problem, the team constructed a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumor cell membrane-selective localization of synthetic receptors to amplify the subsequent targeting of therapeutics. Here, synthetic and biological nanocomponents refer to liposomes and extracellular vesicles, respectively.
The synthetic receptors are first delivered selectively to tumor cell membranes in the perivascular region using liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the synthetic receptors are transferred to neighboring cells and further spread throughout the tumor tissues where the molecular targets are limited.
Hitchhiking extracellular vesicles for delivery of synthetic receptors was possible since extracellular vesicles, such as exosomes, mediate intercellular communications by transferring various biological components such as lipids, cytosolic proteins, and RNA through a membrane fusion process. They also play a supportive role in promoting tumor progression in that tumor-derived extracellular vesicles deliver oncogenic signals to normal host cells.
The team showed that this tumor cell membrane-targeted delivery of synthetic receptors led to a uniform distribution of synthetic receptors throughout a tumor and subsequently led to enhanced phototherapeutic efficacy of the targeted photosensitizer.
Professor Park said, “The cooperative tumor targeting system is expected to be applied in treating various diseases that are hard to target.”
The research was funded by the Basic Science Research Program through the National Research Foundation funded by the Ministry of Science, ICT & Future Planning, and the National R&D Program for Cancer Control funded by the Ministry for Health and Welfare.
(Ph.D. candidates Hee Gon Kim (left) and Chanhee Oh)
Figure 1. A schematic of a cooperative tumor targeting system via delivery of synthetic receptors.
Figure 2. A confocal microscopic image of a tumor section after cooperative targeting by synthetic receptor delivery. Green and magenta represent vessels and therapeutic agents inside a tumor respectively.
2017.07.07 View 10728 -
Reform of Universities Key in the Wake of the 4th Industrial Revolution
(President Shin makes a keynote speech at the Times Higher Education Research Excellence Summit held in Taiwan on July 4.)
KAIST President Sung-Chul Shin stressed that innovations in education, research, and technology commercialization of universities are critical for responding to the transformations that the Fourth Industrial Revolution will bring about.
In his keynote speech at the Times Higher Education Research Excellence Summit held in Taiwan on July 4, he cited connectivity, superintelligence, and convergence in science and technology as three components the Fourth Industrial Revolution will pierce, saying the speed and breadth of the transformation will be beyond our imagination. He also presented megatrends in science and technology in the years to come and how KAIST is addressing the challenges and opportunities.
“It is imperative to foster creative young talents fluent in convergence, collaboration, and communication skills in the new era. To this end, we need to focus on whole brain education by enhancing basic education in science and engineering plus humanities and social studies,” he stressed. He also presented a Non-Departmental Education Track, which KAIST plans to implement from next semester. The track, designed to prepare students for the new industrial era, will focus on whole brain education including entrepreneurship and leadership education during the undergraduate period.
He also emphasized an effective new teaching methodology. “We need to develop various new teaching methods. The paradigm should shift from lecturer-centered to student-centered. KAIST is revising our curriculum to facilitate team-based, project-based learning and flipped learning,” he explained.
President Shin also pointed out that the educational goals for the next generation should be to sustain the value of people’s own thoughtfulness, wisdom, emotion, and caring against the advent of a new tribe of AI, dubbed Robo Sapiens. “Those traits add undeniable educational value that we should continue to pursue even in the era of Robo Sapiens,” he added.
As for research innovation, he emphasized inter- and multi-disciplinary collaborative research. “Especially, in addressing pressing global issues and big science, international collaboration will be very effective and crucial,” he said.
At the summit, convergence research projects currently underway at KAIST using emerging technologies such as the smart mobile healthcare project, Dr, M; the humanoid robot, HUBO; and AI drone swarms drew lots of attention from the participants, even receiving proposals to join the projects as collaborators.
In the new era, according to Shin, technology commercialization at universities will emerge as a hub of R&DB. Citing that KAIST has long been a draw for startups, he noted that KAIST has also set a high value on entrepreneurship education including social entrepreneurship and startups.
He continued, “The Korean government is making every effort to harness the challenges and opportunities of the Fourth Industrial Revolution by creating a new economic growth engine. For the success of the government initiative, universities should also respond to make innovations commensurate with the changing needs and challenges. KAIST will take the lead in this new initiative for making a new future.”
2017.07.06 View 7318 -
Mutations Unveiled that Predispose Lung Cancer Cells to Refractory Histologic Transformation
Cancer pedigree analysis reveals the mutations in RB1 and TP53 genes play a key role in treatment-resistant, cancer cell-type transformation during EGFR inhibitor therapy for lung cancers.
Research led by Korean medical scientists has discovered that a specific type of drug resistance mechanism to EGFR inhibitor therapy in lung cancer is predisposed by mutations in two canonical cancer-related genes: RB1 and TP53. Published in Journal of Clinical Oncology on May 12, the study also found those mutations can be detectable in patients' tumors at the point of clinical diagnosis. Therefore, it can be used as strong markers in clinic for predicting poor outcome for the targeted treatment for lung adenocarcinoma.
Lung adenocarcinoma is the most common type of lung cancer, and about 15% of patients in Western countries and 50% of patients in Asian countries have mutations in the EGFR gene, which is critical for the development of lung cancer. Patients with lung adenocarcinoma harboring the EGFR mutation show favorable responses to EGFR inhibitors such as erlotinib (Tarceva) or gefitinib (Iressa), but ultimately relapse with drug-resistant tumors. Since the initial report in 2006, it has been known that in about 5~15% of patients, the lung adenocarcinoma cells undergo a mysterious transformation into a very different cancer cell type called “small cell lung cancer,” a much more aggressive lung cancer subtype, common in cigarette smokers.
To find out the genetic basis of this process, the researchers compared the genome sequences of multiple cancer tissues acquired during the treatment courses of patients whose tumors underwent small-cell transformation. They reconstructed the cancer cell pedigree by comparing mutations between cancer tissues, and identified that RB1 and TP53 genes are completely inactivated by mutations already in their lung adenocarcinoma tissues.
"We tried to compare the somatic mutational profile of pre-EGFR inhibitor treatment lung adenocarcinomas and post-treatment small cell carcinomas and to reconstruct the pedigrees of the cancer evolution in each patient. Strikingly, both copies of RB1 and TP53 genes were already inactivated at the stage of lung adenocarcinomas in all sequenced cases," said Dr. Jake June-Koo Lee, the first author from KAIST.
They further pursued the clinical implications of RB1 and TP53 inactivation by investigating 75 EGFR-mutated lung adenocarcinoma tissues from patients who received EGFR inhibitor therapy, including patients with small-cell transformation. In this analysis, the lung adenocarcinomas with a complete inactivation of both RB1 and TP53 genes tended to have a 43-times greater risk of transformation into small cell lung cancer during their EGFR inhibitor treatment courses.
Dr. Young Seok Ju, the co-last author from KAIST, explained, "This study shows the power of entire genome analyses to better understand the mechanisms underlying mysterious phenomenon encountered in clinic. Upon accurate bioinformatics, we are finding cancer-specific somatic mutations from the whole-genomes of patients’ cancer cells. These mutations allow us to track the evolution of cancer cells throughout the extraordinary clinical course of a special set of lung cancers."
The complete inactivation of both RB1 and TP53 tumor suppressor genes is found in a minor (<10%) subset of lung adenocarcinoma. This study suggests that the clinical course against targeted therapy is endogenously different for the cancers in the subgroup, and specific drug-resistance mechanisms are predisposed by the two genetic mutations. Indeed, RB1 and TP53 double inactivation is a genetic hallmark of primary small cell lung cancer, observed in nearly all cases.
"We are actively investigating patient tumor tissues to develop optimal surveillance plans and treatment options for patients with lung adenocarcinomas more prone to small-cell transformation," said Dr. Tae Min Kim, the co-last author from Seoul National University Hospital.
The researchers are implementing their findings into lung cancer clinics by screening the RB1 and TP53 mutational status in lung adenocarcinoma patients receiving EGFR inhibitor treatment, and following their treatment courses to develop a treatment strategy for those patients.
This research (doi.org/10.1200/JCO.2016.71.9096) was funded by the National Research Foundation of Korea (NRF-2013H1A2A1032691 to J.-K.L., NRF-2014R1A2A2A05003665 to Y.T.K.); Korea Institute of Science and Technology Information (K-16-L03-C02-S02 to J.L.); and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, which was funded by the Ministry of Health and Welfare (HI14C1234 to T.M.K., HI16C2387 to Y.S.J.)
Figure. Phylogeny analysis of serially-acquired tumors
A. Phylogeny trees of sequenced cases (LC1−LC4) are reconstructed from the WGS data. Conceptual illustrations are depicted with grey color. Circles indicate major clones of the tumors. The length of each branch is proportional to the number of mutations that occurred in the branch. Mutations of cancer-related genes in each branch are indicated with arrows. The time points of relevant treatments are summarized below the trees.
B. Mutations of RB1 and TP53 in two early LADCs (LC1b and LC4a) are visualized using Integrative Genomics Viewer (left panel). Allele-specific copy number analysis shows loss of heterozygosity of chromosomes 13 and 17 in both early LADCs and EGFR TKI-resistant SCLCs (right panel).
C. Clonal evolution of LC1 is described with clinical history and tumor volumes. The horizontal axis represents the time from the diagnosis (0), and the vertical axis indicates the volume of tumors calculated from the computed tomography images.
Abbreviations: LADC, lung adenocarcinoma; SCLC, small cell lung cancer
2017.06.07 View 8718 -
Bio-based p-Xylene Oxidation into Terephthalic Acid by Engineered E.coli
KAIST researchers have established an efficient biocatalytic system to produce terephthalic acid (TPA) from p-xylene (pX). It will allow this industrially important bulk chemical to be made available in a more environmentally-friendly manner.
The research team developed metabolically engineered Escherichia coli (E.coli) to biologically transform pX into TPA, a chemical necessary in the manufacturing of polyethylene terephthalate (PET). This biocatalysis system represents a greener and more efficient alternative to the traditional chemical methods for TPA production. This research, headed by Distinguished Professor Sang Yup Lee, was published in Nature Communications on May 31.
The research team utilized a metabolic engineering and synthetic biology approach to develop a recombinant microorganism that can oxidize pX into TPA using microbial fermentation. TPA is a globally important chemical commodity for manufacturing PET. It can be applied to manufacture plastic bottles, clothing fibers, films, and many other products. Currently, TPA is produced from pX oxidation through an industrially well-known chemical process (with a typical TPA yield of over 95 mol%), which shows, however, such drawbacks as intensive energy requirements at high temperatures and pressure, usage of heavy metal catalysts, and the unavoidable byproduct formation of 4-carboxybenzaldehyde.
The research team designed and constructed a synthetic metabolic pathway by incorporating the upper xylene degradation pathway of Pseudomonas putida F1 and the lower p-toluene sulfonate pathway of Comamonas testosteroni T-2, which successfully produced TPA from pX in small-scale cultures, with the formation of p-toluate (pTA) as the major byproduct. The team further optimized the pathway gene expression levels by using a synthetic biology toolkit, which gave the final engineered E. coli strain showing increased TPA production and the complete elimination of the byproduct.
Using this best-performing strain, the team designed an elegant two-phase (aqueous/organic) fermentation system for TPA production on a larger scale, where pX was supplied in the organic phase. Through a number of optimization steps, the team ultimately achieved production of 13.3 g TPA from 8.8 g pX, which represented an extraordinary yield of 97 mol%.
The team has developed a microbial biotechnology application which is reportedly the first successful example of the bio-based production of TPA from pX by the microbial fermentation of engineered E. coli. This bio-based TPA technology presents several advantages such as ambient reaction temperature and pressure, no use of heavy metals or other toxic chemicals, the removable of byproduct formation, and it is 100% environmentally compatible.
Professor Lee said, “We presented promising biotechnology for producing large amounts of the commodity chemical TPA, which is used for PET manufacturing, through metabolically engineered gut bacterium. Our research is meaningful in that it demonstrates the feasibility of the biotechnological production of bulk chemicals, and if reproducible when up-scaled, it will represent a breakthrough in hydrocarbon bioconversions.”
Ph.D. candidate Zi Wei Luo is the first author of this research (DOI:10.1038/ncomms15689).The research was supported by the Intelligent Synthetic Biology Center through the Global Frontier Project (2011-0031963) of the Ministry of Science, ICT & Future Planning through the National Research Foundation of Korea.
Figure: Biotransformation of pX into TPA by engineered E. coli.
This schematic diagram shows the overall conceptualization of how metabolically engineered E. coli produced TPA from pX. The engineered E. coli was developed through reconstituting a synthetic metabolic pathway for pX conversion to TPA and optimized for increased TPA yield and byproduct elimination. Two-phase partitioning fermentation system was developed for demonstrating the feasibility of large-scale production of TPA from pX using the engineered E. coli strains, where pX was supplied in the organic phase and TPA was produced in the aqueous phase.
2017.06.05 View 11530 -
Observation of the Phase Transition of Liquid Crystal Defects
KAIST researchers observed the phase transition of topological defects formed by liquid crystal (LC) materials for the first time.
The phase transition of topological defects, which was also the theme of the Nobel Prize for Physics in 2016, can be difficult to understand for a layperson but it needs to be studied to understand the mysteries of the universe or the underlying physics of skyrmions, which have intrinsic topological defects.
If the galaxy is taken as an example in the universe, it is difficult to observe the topological defects because the system is too large to observe some changes over a limited period of time. In the case of defect structures formed by LC molecules, they are not only a suitable size to observe with an optical microscope, but also the time period in which the phase transition of a defect occurring can be directly observed over a few seconds, which can be extended to a few minutes. The defect structures formed by LC material have radial, circular, or spiral shapes centering on a singularity (defect core), like the singularity that was already introduced in the famous movie "Interstellar,” which is the center point of black hole.
In general, LC materials are mainly used in liquid crystal displays (LCDs) and optical sensors because it is easy to control their specific orientation and they have fast response characteristics and huge anisotropic optical properties. It is advantageous in terms of the performance of LCDs that the defects of the LC materials are minimized. The research team led by Professor Dong Ki Yoon in the Graduate School of Nanoscience and Technology did not simply minimize such defects but actively tried to use the LC defects as building blocks to make micro- and nanostructures for the patterning applications. During these efforts, they found the way to directly study the phase transition of topological defects under in-situ conditions.
Considering the LC material from the viewpoint of a device like a LCD, robustness is important. Therefore, the LC material is injected through the capillary phenomenon between a rigid two-glass plate and the orientation of the LCs can be followed by the surface anchoring condition of the glass substrate. However, in this conventional case, it is difficult to observe the phase transition of the LC defect due to this strong surface anchoring force induced by the solid substrate.
In order to solve this problem, the research team designed a platform, in which the movement of the LC molecules was not restricted, by forming a thin film of LC material on water, which is like oil floating on water. For this, a droplet of LC material was dripped onto water and spread to form a thin film. The topological defects formed under this circumstance could show the thermal phase transition when the temperature was changed. In addition, this approach can trace back the morphology of the original defect structure from the sequential changes during the temperature changes, which can give hints to the study of the formation of topological defects in the cosmos or skyrmions.
Prof. Yoon said, “The study of LC crystal defects itself has been extensively studied by physicists and mathematicians for about 100 years. However, this is the first time that we have observed the phase transition of LC defects directly.” He also added, "Korea is leading in the LCD industry, but our basic research on LCs is not at the world's research level."
The first author of this study is Dr. Min-Jun Gimand supported by a grant from the National Research Foundation (NRF) and funded by the Korean Government (MSIP). The research result was published on May 30, 2017 in Nature Communications.
Figure 1. The phase transition of the LC topological defect on cooling.
Figure 2. Polarizing optical microscopy images of topological defects depending on the strength of the director field. (a,b,e) Convergent director field arrangements of LC molecules and corresponding schematic images; (c,d,f) Divergent director field arrangements of LC molecules and corresponding schematic images.
2017.06.02 View 9734