Shenzhen Bay Laboratory has made a series of important progress in esophageal squamous cell carcinoma research

Esophageal cancer is one of the world’s most common malignant tumors, China’s esophageal cancer incidence and mortality are ranked first in the world, the latest statistics show that in China every year about 480,000 new esophageal cancer cases, 370,000 esophageal cancer patients died. Europe and the United States and China esophageal cancer pathological classification is different, Europe and the United States to adenocarcinoma dominoma, and China more than 90% is squamous cell carcinoma (ESCC), more than 50% of the world’s ESCC occurs in China, due to different pathological classification, foreign theoretical and clinical research is not suitable for guiding the diagnosis and treatment of Chinese esophageal cancer patients. ESCC has the characteristics of high heterogeneity, rapid progression, poor prognosis and obvious regional morbidity, and early patients lack specific symptoms, are mostly in the middle and late stages at the first visit, and have a low 5-year survival rate. Although traditional surgery, radiotherapy and chemotherapy have made great progress, their efficacy is limited, and the lack of effective targeted therapy drugs makes local recurrence and distant metastasis still important reasons for ESCC treatment failure. The key reason limiting the improvement of ESCC diagnosis and treatment in China is insufficient understanding of the basis of molecular variation, molecular typing and tumor microenvironment.

Facing the major needs of the country, with the support of the national and Guangdong Province basic and applied infrastructure major projects, the team of Academician Zhan Qimin / Professor Cui Yongping of Shenzhen Bay Laboratory focused on esophageal squamous cell carcinoma, a highly common malignant tumor in China, through the collaborative research of esophageal squamous cell carcinoma with Professor Liu Zhihua of the Cancer Hospital of the Chinese Academy of Medical Sciences, Professor Huang Canhua of Sichuan University, Professor Zhang Ning of Peking University, Professor Wang Xin of City University of Hong Kong, etc. Multi-level research methods such as cells and model animals, combined with bioinformatics and systems biology analysis, and using a variety of omics techniques, hope to draw the holographic life information map of Chinese group ESCC, reveal the molecular variation basis of ESCC, decipher its pathogenic mechanism, and establish molecular typing and targeted therapy strategies based on the hologram “according to the diagram” (Figure 1). In recent years, a series of achievements have been made in the basis of molecular variation, molecular typing and target screening of ESCC.

Figure 1 ESCC precision diagnosis and treatment research path

(1) Establish the largest ESCC genome-wide map to reveal the characteristics of molecular variation

Few of the mutated genes in ESCC that have been identified are clinically functional, and the number of approved inhibitors for the treatment of advanced ESCC is very limited, requiring the identification of new ESCC cancer driver genes based on whole genome sequencing (WGS) data and the exploration of other prognostic biomarkers in a larger range of ESCC patients with available clinical data. On May 12, 2020, the team of Academician Zhan Qimin / Professor Cui Yongping cooperated with Shanxi Medical University, Cancer Hospital of Chinese Academy of Medical Sciences, Peking University Statistical Science Center, Peking University Cancer Hospital, Shenzhen Peking University of Science and Technology Medical Center, Baidu Company and others to complete a large-scale esophageal squamous cell carcinoma (ESCC) genomics research result, which was published in Cell Research with the title of “Whole-genome sequencing” of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma”。 In this study, the whole genome sequencing of 508 esophageal squamous cell carcinoma patients from Shanxi and Xinjiang was carried out, and the genetic map of the genetic changes of driver genes in coding and non-coding regions was established, and five new significant mutant genes related to cancer metastasis and patient prognosis were identified. The classification of ESCC into three subtypes: NFE2L2 mutation, RTK-RAS-MYC amplification and double negative strongly predicted the prognostic survival of ESCC patients. This study utilizes deep whole genome sequencing from a large cohort of Chinese patients to provide the most comprehensive ESCC genome characterization to date, reveals the molecular pathological mechanism of ESCC, and further lays the foundation for the subsequent development of specific biomarkers that can be used for the diagnosis and treatment of ESCC (Figure 2).

Figure 2 A comprehensive map of molecular variation of coding and non-coding genes of ESCC

(2) Identify complex structural variants of ESCC and deepen the understanding of genetic variation of ESCC

Based on gene sequencing technology, the driver mutation, mutation process and key pathway/cloning kinetics in the process of ESCC tumorigenesis were revealed to a certain extent. However, the current analysis of genomic structural variants (SVs) and their mechanisms is still limited. In response to this problem, the team of Academician Zhan Qimin / Professor Cui Yongping conducted in-depth research and hoped to further reveal the pathogenic mechanism of ESCC. On October 22, 2022, the team, together with collaborators such as Cancer Hospital of Chinese Academy of Medical Sciences, Shanxi Medical University, Peking University Cancer Hospital, Shenzhen Peking University, and Hong Kong University of Science and Technology Medical Center, published a title entitled “Characterization of somatic structural variations in 528 Chinese individuals” in Nature Communications with Esophageal squamous cell carcinoma”. In order to reveal the complex structural variation (SV) characteristics of the ESCC genome, the team developed the complex SV detection method FindRear, which analyzed the genome structural variation at the population level on the whole genome sequencing data of 528 pairs (cancer and adjacent paired tissues), and systematically elaborated the structural variation types of ESCC, including TDP (tandem duplication phenotype), Insertion, Inversion, fusion genotyping, etc and in-depth analysis of extrachromosomal circular DNA (ecDNA), Katagsis, and chromosomal fragmentation. This study is the first to identify that ESCC has structural mutation events at a very early stage and is a tumor with a high SV burden, in which tandem duplication of TD-c2 and ecDNA is an important factor in oncogene amplification. It is worth mentioning that this study has found a novel mechanism of super-enhancer formation, which exists in a specific oncogene enhancer region to form super-enhancers in the form of enhancer tandem repeats, which is also an important mechanism leading to oncogene overexpression, which expands the understanding of super-enhancers (Figure 3).

Fig. 3 Genome-wide analysis of large samples revealed the structural variation map and mechanism of ESCC

(3) Analysis of the genetic and epigenetic mechanisms of ESCC chemotherapy resistance

Tumor heterogeneity is key to drug resistance and recurrence. The paper entitled “Genomic and epigenomic evolution of acquired resistance to combination therapy in esophageal squamous cell carcinoma” published in JCI Insight on September 8, 2021 shows that Patients with ESCC who progressed after receiving chemotherapy showed significantly higher genomic and epigenomic temporal heterogeneity. Resistance-mediated subclonal amplification of new mutations was observed during chemotherapy in combination with verapamil. SLC7A8 was found to be a potential new multidrug resistance (MDR) gene, and functional analysis showed that the mutant SLC7A8 promoted the drug-resistant phenotype of ESCC cell lines. Promoter methylation dynamics during treatment showed that the promoter regions of the 8 drug-resistant protein-coding genes had a low degree of methylation. Interestingly, promoter hypomethylation of SLC8A3 and mutant SLC7A8 is enriched by the same pathway, i.e., protein digestion and absorption, suggesting that a novel MDR mechanism may exist during treatment. This study integrates multi-omics data to reveal inter- and intratumor-tumor heterogeneity, clonal evolution, and epigenomic changes in time series and epigenetics, providing potential MDR therapeutic targets for ESCC-resistant patients during combination therapy (Figure 4).

Fig. 4 Multiomics techniques reveal a new mechanism of ESCC chemotherapy resistance

(4) Establish an ESCC molecular typing system to guide precision treatment

Precision therapy guided by molecular typing has achieved remarkable results in the clinical practice of breast cancer, colorectal cancer, gastric cancer, lung cancer, liver cancer and other solid tumors, effectively improving the survival of patients. However, there is no robust molecular typing of ESCC at present, because most of the previous studies have started from a single omics and the number of sample cases is small, which has only revealed a limited number of molecular variation characteristics of ESCC. Therefore, excavating the pathogenic mechanism of ESCC from multi-omics and multi-level perspectives, clarifying its molecular typing, and improving its high diagnosis and treatment level have become a major research topic in the field of esophageal squamous cell carcinoma. On December 29, 2022, the team, together with Cancer Hospital of Chinese Academy of Medical Sciences, Shanxi Medical University, and Peking University Cancer Hospital, published the article “Integrated Multi-omics Profiling Yields a Clinically-Relevant Molecular Classification for Esophageal Squamous Cell” in Cancer Cell Carcinoma”。 Based on multiomics data analysis, the researchers divided ESCC into four molecular subtypes: cell cycle pathway activation (CCA), NRF2 pathway activation (NRFA), immunosuppressive (IS) and immunomodulatory (IM). This is the first international ESCC classification based on multiomics data, and potential therapeutic targets and/or diagnostic markers are sought for each subtype.

The researchers included 155 paired samples of ESCC patients for comprehensive integrated analysis at the level of genome-wide, epigenomic, transcriptome and proteome data. Multiomics analysis was used to divide ESCC into four subtypes for the first time: CCA, NRFA, IS, and IM (Figure 4). The CCA subtype is manifested in variations in cell cycle checkpoint genes, while the NRFA subtype has activation of NRF2 pathway genes. Patients with both CCA and NRFA subtypes have a CpG island methylation phenotype (E-CIMP+) and are associated with lymphatic node metastasis and clinical stage. The IS and IM subtypes are highly invasive immune cells, but the types of immune cells infiltrated by tumor tissue are different. The researchers further used the cohort study of 43 patients receiving PD-1 antibody monotherapy to find that the IM subtype had a better treatment response to immune checkpoint blockade therapy (ICB), and based on the multiomics data of the ESCC tissue of the cohort, a molecular feature classifier was developed to identify patients with IM subtype, reflecting the multiomics based on multi-omics numbersAccording to the clinical value of molecular typing. In general, this study established the ESCC multi-omics molecular typing system for the first time, and the unique molecular characteristics of different subtypes are the “course” of clinical transformation, breaking the difficulty of the “ambiguous direction” of ESCC treatment in the past, and helping medical experts to “prescribe the right medicine”, which is expected to truly elevate the diagnosis and treatment of ESCC to the level of precision medicine and improve the survival benefits of patients. The team will carry out drug development and clinical experimental research for each subtype of ESCC, realize clinical transformation as soon as possible, formulate treatment strategies for different subtypes of ESCC, and let patients enter the era of precision treatment based on ESCC molecular typing as soon as possible.

Fig. 5 Multiomics molecular tetratyping of esophageal squamous cell carcinoma and its potential therapeutic targets

In addition to the above research on the basis of molecular variation and molecular typing, the team has also achieved fruitful results in the molecular mechanism and potential therapeutic targets of ESCC occurrence and development, identifying FAM135B, MAGE-C3, NOX5, FAK, lncRNA VESTAR, cir-PUM1 and a series of key factors regulating the malignant progression of ESCC, and analyzing their molecular mechanisms, providing potential therapeutic targets for clinical treatment. The research has been published in Signal Transduction and Targeted Therapy (2022), Cancer Research (2021), Cellular & Molecular Immunology (2022), Cancer Communications (2021), Clinical and Translational Medicine(2021)。

In summary, based on the solid research foundation and extensive and close cooperative relationship in the past, the team of Zhan Qimin/Cui Yongping of Shenzhen Bay Laboratory has achieved a series of results around esophageal squamous cell carcinoma, a high-incidence characteristic malignant tumor in China, and continuously supplemented the molecular variation puzzle and regulatory network diagram of esophageal squamous cell carcinoma, providing a rich theoretical basis for formulating the “Chinese program” for esophageal squamous cell carcinoma.

The above research has been funded by the National Key R&D Program, the National Natural Science Foundation of China, the Guangdong Basic and Applied Foundation Major Project, the Shenzhen Bay Laboratory Major Project, Baidu Foundation, the Guangdong Provincial Natural Foundation, the Shenzhen Science and Technology Innovation Commission and other related funds, and also received the selfless and strong support of every patient and family who participated in the research.

Figure 6 Group photo of Academician Zhan Qimin and Cui Yongping’s research team in Shenzhen Bay Laboratory

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