The research group primarily focuses on the development of colorectal cancer, conducting research in the fields of tumor epigenetics, clinical proteomics, and translational medicine. We have undertaken 10 projects funded by the National Natural Science Foundation, 6 projects funded by provincial and ministerial-level research funds, and the Guangdong Provincial Outstanding Youth Program Grant. We have also participated in National Basic Research Program (973 projects), and National Key Research and Development Program of China.

Research Achievements: We made several groundbreaking discoveries in their research. They were the first to find that DNA methylation plays a crucial role in the transformation process from colorectal adenoma (CRA) to colorectal cancer (CRC) by inhibiting microtubule aggregation when binding to free Tubulin. We also identified the microtubule binding site, which provides important intervention targets for preventing tumor development and treatment.

We introduced a novel mechanism of DNA methylation regulation in adenoma carcinogenesis. They found that only tubular/villous adenomas with high methylation levels could progress into adenocarcinomas (published in Gastroenterology, 2014, IF=29.4). DNA methylation was shown to "silence" tumor suppressor gene expression through epigenetics, promoting the malignant characteristics of normal colonic mucosal epithelial cells and increasing the invasive capacity of tumor cells. This discovery highlighted the key molecular events controlling cellular behavior. We also innovatively found that the INA protein exerts anti-cancer effects by binding to free Tubulin to inhibit microtubule aggregation. They identified the microtubule binding site, providing scientific evidence for how DNA methylation specifically promotes colorectal cancer progression (published in Cancer Research, 2020, IF=11.2).

Research Achievements: We developed a novel DNA methylation detection technology known as QASM. We have used this technology to systematically elucidate the DNA methylation characteristics of early-stage CRC (colorectal cancer), providing valuable insights that can be applied to assess the risk of recurrence in early-stage CRC and offering important targets for the evaluation and prognosis of CRC.

Our QASM technology is a state-of-the-art method for detecting individual DNA methylation sites with exceptional accuracy and efficiency. It has significantly improved the precision of DNA methylation detection, narrowing it down to 2 base pairs, making it an internationally leading technology in this field. This innovation has been granted national invention patents (patent number 201810845927.3) and was selected as one of the "High-Value Patent Projects" in China in 2021, further promoting its clinical translation and application.

In the context of predicting chemotherapy sensitivity using DNA methylation biomarkers, our research team conducted large-scale prospective clinical studies. In these studies, we made a groundbreaking discovery that for stage 3 CRC patients with intact mismatch repair genes, chemotherapy regimens containing cetuximab significantly extended patients' survival time. This finding underscored the strong correlation between DNA methylation and the biological behavior of tumors, particularly in the context of chemotherapy sensitivity (Clinical Cancer Research, 2016, IF=11.5; Gastroenterology, 2014, IF=29.4).

We also investigated the role of DNA methylation in the biological behavior of early-stage colorectal cancer, especially in cases where chemotherapy is not required. Using whole-genome DNA methylation scanning technology, our research team identified four novel DNA methylation sites and constructed the MePEC model. We found that MePEC scores were closely associated with postoperative recurrence and metastasis in early-stage CRC. However, these four sites were located in regions that are challenging to detect using conventional methylation PCR techniques. Subsequently, we successfully designed a clinical PCR detection system using the QASM technology and validated it in samples from international multicenter studies. The research results were published in the oncology journal JNCI (Journal of the National Cancer Institute, 2023, IF=10.3), accompanied by a commentary from Professor Romesser, Chief Scientist of Cancer Treatment at the Sloan Kettering Cancer Center in the United States, highlighting that our study provides a novel, efficient, and reliable approach for predicting the risk of early-stage colorectal cancer and offers significant new targets for cancer treatment (Journal of the National Cancer Institute. 2023;115(1):8-11).

Research Achievements: From the perspective of DNA methylation, our research has explored the impact of the tumor microenvironment on the biological behavior of CRC. We systematically described, for the first time, the DNA methylation characteristics of infiltrating CD8+ T lymphocytes in the tumor microenvironment. This can be used to assess the immune response in CRC. Furthermore, we discovered that DNA methylation regulates M2-type tumor-associated macrophages (TAMs) in the microenvironment, along with other biological behaviors such as energy metabolism and tumor chemotherapy resistance.

Our research group, focusing on DNA methylation, has explored the impact of the tumor microenvironment on the biological behavior of tumors. We initially evaluated infiltrating CD8+ T lymphocytes in tumors using classic immunohistochemistry. Subsequently, we utilized methylation chip data from CD8+ T cells, CRC cells, normal colon epithelial cells, and other immune cells from the human body. We identified specific methylation differences in CD8+ T cells, which efficiently distinguished them from other cell types. Building upon this, we developed the "CD8+ MeTIL" scoring system. We employed our in-house developed QASM technology for detection. We evaluated the anti-tumor immune characteristics and treatment outcomes in CRC patients at Sun Yat-sen University Cancer Center (SYSUCC) and clinical cohorts from North America, including the Fred Hutchinson Cancer Research Center, Mayo Clinic, and Mount Sinai Medical Center. Our findings revealed that CD8+ MeTIL is capable of effectively stratifying CRC patients based on their risk of mortality, as published in the Journal for ImmunoTherapy of Cancer in 2021 (IF=10.9).

In addition, our research has revealed that DNA methylation not only directly controls the biological behavior of tumor cells but also modulates immune cells in the tumor microenvironment. DNA methylation downregulates CSF1R in colon cancer, and CRC cells that re-express CSF1R compete with M2-type TAMs for CSF1R ligands, leading to decreased activation and proliferation of TAMs. Blocking CSF1R with the specific inhibitor PLX3397 can reduce M2 TAMs and increase CD8+ T cell infiltration in the tumor microenvironment, effectively inhibiting tumor growth and metastasis and enhancing the response to immunotherapy. These findings provide new evidence for the key molecular mechanisms of DNA methylation in regulating the tumor microenvironment and influencing clinical treatment outcomes (published in the Journal for ImmunoTherapy of Cancer, 2022, IF=10.9).

The biological behavior of tumors is also highly influenced by the metabolic conditions of the microenvironment. We found that during a fasting-mimicking diet (FMD), CRC cells transition from active proliferation to slow proliferation, accompanied by a significant reduction in cellular metabolism. However, FMD treatment, while significantly reducing cell proliferation, does not increase sensitivity to anti-tumor drugs like 5-FU. FMD treatment leads to CRC cells entering a dormant state, making them more likely to form persistent drug-resistant cells, which have been confirmed as essential factors in tumor recurrence and metastasis. Through UMI-mRNA analysis, our research group found significant changes in the expression of iron-related genes in CRC cells after FMD treatment. Experimental results showed that combining FMD with iron death inducers and chemotherapy can more effectively inhibit tumor growth. This innovative finding suggests that combining FMD with iron death inducers can further enhance the anti-tumor effect, providing a new theoretical basis for CRC treatment (published in eBioMedicine, 2023, IF=11.1).

In summary, our research group has systematically elucidated the DNA methylation characteristics of infiltrating CD8+ T lymphocytes in the tumor microenvironment from a DNA methylation perspective. We have also investigated how changes in the microenvironment's energy metabolism affect tumor chemotherapy resistance. We have validated these findings in large clinical samples and established new, stable, and reliable testing technologies, providing new strategies and methods for clinical translation.

Research Achievements: We discovered that contracting COVID-19 may accelerate epigenetic aging clocks and telomere attrition, promoting epigenetic aging and potentially leading to post-COVID-19 sequelae (published in Nature Communications, 2022, IF=16.6).

Our research team conducted DNA methylation analyses using the EPIC methylation array on blood samples from 232 healthy individuals and 413 COVID-19 patients. Subsequently, we employed five previously established epigenetic clocks (Hannum, Horvath, PhenoAge, skinHorvath, and GrimAge) as well as a telomere length estimator to assess the epigenetic age of whole blood samples from COVID-19 patients and healthy individuals. The results indicated a strong correlation between epigenetic clocks and an individual's actual age. In the blood samples of healthy individuals, non-severe COVID-19 patients, and severe COVID-19 patients, the rate of epigenetic aging and telomere attrition increased progressively.

Furthermore, longitudinal DNA methylation profiling revealed that in some patients during the COVID-19 recovery period, the accumulation of epigenetic aging induced by COVID-19 infection might partially reverse. These research findings, in conjunction with other laboratory tests and clinical observations, contribute to the identification of COVID-19 patients at risk of developing severe symptoms and potential post-COVID-19 complications, thereby facilitating the provision of improved treatment and care strategies (published in Nature Communications, 2022, IF=16.6).