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KAIST Discovers Molecular Switch that Reverses Cancerous Transformation at the Critical Moment of Transition
< (From left) PhD student Seoyoon D. Jeong, (bottom) Professor Kwang-Hyun Cho, (top) Dr. Dongkwan Shin, Dr. Jeong-Ryeol Gong >
Professor Kwang-Hyun Cho’s research team has recently been highlighted for their work on developing an original technology for cancer reversal treatment that does not kill cancer cells but only changes their characteristics to reverse them to a state similar to normal cells. This time, they have succeeded in revealing for the first time that a molecular switch that can induce cancer reversal at the moment when normal cells change into cancer cells is hidden in the genetic network.
KAIST (President Kwang-Hyung Lee) announced on the 5th of February that Professor Kwang-Hyun Cho's research team of the Department of Bio and Brain Engineering has succeeded in developing a fundamental technology to capture the critical transition phenomenon at the moment when normal cells change into cancer cells and analyze it to discover a molecular switch that can revert cancer cells back into normal cells.
A critical transition is a phenomenon in which a sudden change in state occurs at a specific point in time, like water changing into steam at 100℃. This critical transition phenomenon also occurs in the process in which normal cells change into cancer cells at a specific point in time due to the accumulation of genetic and epigenetic changes.
The research team discovered that normal cells can enter an unstable critical transition state where normal cells and cancer cells coexist just before they change into cancer cells during tumorigenesis, the production or development of tumors, and analyzed this critical transition state using a systems biology method to develop a cancer reversal molecular switch identification technology that can reverse the cancerization process. They then applied this to colon cancer cells and confirmed through molecular cell experiments that cancer cells can recover the characteristics of normal cells.
This is an original technology that automatically infers a computer model of the genetic network that controls the critical transition of cancer development from single-cell RNA sequencing data, and systematically finds molecular switches for cancer reversion by simulation analysis. It is expected that this technology will be applied to the development of reversion therapies for other cancers in the future.
Professor Kwang-Hyun Cho said, "We have discovered a molecular switch that can revert the fate of cancer cells back to a normal state by capturing the moment of critical transition right before normal cells are changed into an irreversible cancerous state."
< Figure 1. Overall conceptual framework of the technology that automatically constructs a molecular regulatory network from single-cell RNA sequencing data of colon cancer cells to discover molecular switches for cancer reversion through computer simulation analysis. Professor Kwang-Hyun Cho's research team established a fundamental technology for automatic construction of a computer model of a core gene network by analyzing the entire process of tumorigenesis of colon cells turning into cancer cells, and developed an original technology for discovering the molecular switches that can induce cancer cell reversal through attractor landscape analysis. >
He continued, "In particular, this study has revealed in detail, at the genetic network level, what changes occur within cells behind the process of cancer development, which has been considered a mystery until now." He emphasized, "This is the first study to reveal that an important clue that can revert the fate of tumorigenesis is hidden at this very critical moment of change."
< Figure 2. Identification of tumor transition state using single-cell RNA sequencing data from colorectal cancer. Using single-cell RNA sequencing data from colorectal cancer patient-derived organoids for normal and cancerous tissues, a critical transition was identified in which normal and cancerous cells coexist and instability increases (a-d). The critical transition was confirmed to show intermediate levels of major phenotypic features related to cancer or normal tissues that are indicative of the states between the normal and cancerous cells (e). >
The results of this study, conducted by KAIST Dr. Dongkwan Shin (currently at the National Cancer Center), Dr. Jeong-Ryeol Gong, and doctoral student Seoyoon D. Jeong jointly with a research team at Seoul National University that provided the organoids (in vitro cultured tissues) from colon cancer patient, were published as an online paper in the international journal ‘Advanced Science’ published by Wiley on January 22nd.
(Paper title: Attractor landscape analysis reveals a reversion switch in the transition of colorectal tumorigenesis) (DOI: https://doi.org/10.1002/advs.202412503)
< Figure 3. Reconstruction of a dynamic network model for the transition state of colorectal cancer.
A new technology was established to build a gene network computer model that can simulate the dynamic changes between genes by integrating single-cell RNA sequencing data and existing experimental results on gene-to-gene interactions in the critical transition of cancer. (a). Using this technology, a gene network computer model for the critical transition of colorectal cancer was constructed, and the distribution of attractors representing normal and cancer cell phenotypes was investigated through attractor landscape analysis (b-e). >
This study was conducted with the support of the National Research Foundation of Korea under the Ministry of Science and ICT through the Mid-Career Researcher Program and Basic Research Laboratory Program and the Disease-Centered Translational Research Project of the Korea Health Industry Development Institute (KHIDI) of the Ministry of Health and Welfare.
< Figure 4. Quantification of attractor landscapes and discovery of transcription factors for cancer reversibility through perturbation simulation analysis. A methodology for implementing discontinuous attractor landscapes continuously from a computer model of gene networks and quantifying them as cancer scores was introduced (a), and attractor landscapes for the critical transition of colorectal cancer were secured (b-d). By tracking the change patterns of normal and cancer cell attractors through perturbation simulation analysis for each gene, the optimal combination of transcription factors for cancer reversion was discovered (e-h). This was confirmed in various parameter combinations as well (i). >
< Figure 5. Identification and experimental validation of the optimal target gene for cancer reversion. Among the common target genes of the discovered transcription factor combinations, we identified cancer reversing molecular switches that are predicted to suppress cancer cell proliferation and restore the characteristics of normal colon cells (a-d). When inhibitors for the molecular switches were treated to organoids derived from colon cancer patients, it was confirmed that cancer cell proliferation was suppressed and the expression of key genes related to cancer development was inhibited (e-h), and a group of genes related to normal colon epithelium was activated and transformed into a state similar to normal colon cells (i-j). >
< Figure 6. Schematic diagram of the research results. Professor Kwang-Hyun Cho's research team developed an original technology to systematically discover key molecular switches that can induce reversion of colon cancer cells through a systems biology approach using an attractor landscape analysis of a genetic network model for the critical transition at the moment of transformation from normal cells to cancer cells, and verified the reversing effect of actual colon cancer through cellular experiments. >
2025.02.05 View 5521 -
'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.)
2018.08.17 View 8308