Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression

Huang, Kie Kyon; Ma, Haoran; Chong, Roxanne Hui Heng; Uchihara, Tomoyuki; Lian, Benedict Shi Xiang; Zhu, Feng; Sheng, Taotao; Srivastava, Supriya; Tay, Su Ting; Sundar, Raghav; Tan, Angie Lay Keng; Ong, Xuewen; Lee, Minghui; Ho, Shamaine Wei Ting; Lesluyes, Tom; Ashktorab, Hassan; Smoot, Duane; Van Loo, Peter; Chua, Joy Shijia; Ramnarayanan, Kalpana; Lau, Louis Ho Shing; Gotoda, Takuji; Kim, Hyun Soo; Ang, Tiing Leong; Khor, Christopher; Lee, Jonathan Wei Jie; Tsao, Stephen Kin Kwok; Yang, Wei Lyn; Teh, Ming; Chung, Hyunsoo; So, Jimmy Bok Yan; Yeoh, Khay Guan; Tan, Patrick

doi:10.1016/j.ccell.2023.10.004

Cited by 20 publications

(5 citation statements)

References 94 publications

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“…Likewise, higher expression of TCF7 is shown in all the four subtypes of GC regardless of age, gender, stage or TNM factors (Figure 6F ; Supplementary Figure S7 ). To explore the expression of TCF7 and MYB during the clinical GC development, we checked the single-cell RNA-seq of the antrum with intestinal metaplasia (IM) obtained from the patients ( 44 ). IM is known as the condition of pre-malignant gastric mucosa, and to be associated with higher GC risk.…”

Section: Resultsmentioning

confidence: 99%

Integrated enhancer regulatory network by enhancer–promoter looping in gastric cancer

Zhu,

Okabe,

Usui

et al. 2024

NAR Cancer

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Enhancer cis-regulatory elements play critical roles in gene regulation at many stages of cell growth. Enhancers in cancer cells also regulate the transcription of oncogenes. In this study, we performed a comprehensive analysis of long-range chromatin interactions, histone modifications, chromatin accessibility and expression in two gastric cancer (GC) cell lines compared to normal gastric epithelial cells. We found that GC-specific enhancers marked by histone modifications can activate a population of genes, including some oncogenes, by interacting with their proximal promoters. In addition, motif analysis of enhancer–promoter interacting enhancers showed that GC-specific transcription factors are enriched. Among them, we found that MYB is crucial for GC cell growth and activated by the enhancer with an enhancer–promoter loop and TCF7 upregulation. Clinical GC samples showed epigenetic activation of enhancers at the MYB locus and significant upregulation of TCF7 and MYB, regardless of molecular GC subtype and clinicopathological factors. Single-cell RNA sequencing of gastric mucosa with intestinal metaplasia showed high expression of TCF7 and MYB in intestinal stem cells. When we inactivated the loop-forming enhancer at the MYB locus using CRISPR interference (dCas9-KRAB), GC cell growth was significantly inhibited. In conclusion, we identified MYB as an oncogene activated by a loop-forming enhancer and contributing to GC cell growth.

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Section: Resultsmentioning

confidence: 99%

Integrated enhancer regulatory network by enhancer–promoter looping in gastric cancer

Zhu,

Okabe,

Usui

et al. 2024

NAR Cancer

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“…In addition, the identification of novel potential markers of GIM and the innovative GIM-ALI model represent significant contributions to the field, offering a new scene for research and therapeutic intervention. Our findings have significant implications for understanding GIM pathogenesis and its progression to GC, offering potential biomarkers for early detection and targets for therapeutic intervention [ 91 ]. In the future, our research aims to leverage the GIM-ALI model for crucial applications, including drug screening and the development of innovative therapeutic interventions.…”

Section: Discussionmentioning

confidence: 99%

Revealing the pathogenesis of gastric intestinal metaplasia based on the mucosoid air-liquid interface

Liu,

Wen,

et al. 2024

J Transl Med

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Background Gastric intestinal metaplasia (GIM) is an essential precancerous lesion. Although the reversal of GIM is challenging, it potentially brings a state-to-art strategy for gastric cancer therapeutics (GC). The lack of the appropriate in vitro model limits studies of GIM pathogenesis, which is the issue this work aims to address for further studies. Method The air-liquid interface (ALI) model was adopted for the long-term culture of GIM cells in the present work. This study conducted Immunofluorescence (IF), quantitative real-time polymerase chain reaction (qRT-PCR), transcriptomic sequencing, and mucoproteomic sequencing (MS) techniques to identify the pathways for differential expressed genes (DEGs) enrichment among different groups, furthermore, to verify novel biomarkers of GIM cells. Result Our study suggests that GIM-ALI model is analog to the innate GIM cells, which thus can be used for mucus collection and drug screening. We found genes MUC17, CDA, TRIM15, TBX3, FLVCR2, ONECUT2, ACY3, NMUR2, and MAL2 were highly expressed in GIM cells, while GLDN, SLC5A5, MAL, and MALAT1 showed down-regulated, which can be used as potential biomarkers for GIM cells. In parallel, these genes that highly expressed in GIM samples were mainly involved in cancer-related pathways, such as the MAPK signal pathway and oxidative phosphorylation signal pathway. Conclusion The ALI model is validated for the first time for the in vitro study of GIM. GIM-ALI model is a novel in vitro model that can mimic the tissue micro-environment in GIM patients and further provide an avenue for studying the characteristics of GIM mucus. Our study identified new markers of GIM as well as pathways associated with GIM, which provides outstanding insight for exploring GIM pathogenesis and potentially other related conditions.

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“…3B ). For instance, integrated bulk and ST analysis on over 1,000 gastric samples obtained during a prospective 10-year study highlighted the role of microbial dysbiosis and immune cell composition in the progression from intestinal metaplasia to gastric cancer and strategies for identifying patients with intestinal metaplasia with high risk of gastric cancer transformation ( 85 ). Another study that focused on the evolution from preneoplasia to invasive lung adenocarcinoma demonstrated that the infiltration of mast cells, monocytes, and lymphatic endothelial cells decreases during progression, whereas the frequency of tumor-infiltrating NK cells and mucosal-associated B cells increases from in situ to minimally invasive adenocarcinoma, and the presence of Tregs and secretory B cells augments from minimally invasive to invasive cancer ( 86 ).…”

Section: St and Sp Analysis Of The Timementioning

confidence: 99%

Spatial Dissection of the Immune Landscape of Solid Tumors to Advance Precision Medicine

Di Mauro,

Arbore

2024

Cancer Immunology Research

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Chemotherapeutics, radiation, targeted therapeutics and immunotherapeutics each demonstrate clinical benefits for a small subset of patients with solid malignancies. Immune cells infiltrating the tumor and the surrounding stroma play a critical role in shaping cancer progression and modulating therapy response. They do this by interacting with the other cellular and molecular components of the tumor microenvironment (TME). Spatial multi-OMICs technologies are rapidly evolving. Currently, such technologies allow high-throughput RNA and protein profiling and retain geographical information about the TME cellular architecture and the functional phenotype of tumor, immune and stromal cells. An in-depth spatial characterization of the heterogenous tumor immune landscape can improve not only the prognosis, but also the prediction of therapy response, directing cancer patients to more tailored and efficacious treatments. This review highlights recent advancements in spatial transcriptomics and proteomics profiling technologies and how these technologies are being applied for the dissection of the immune cell composition in solid malignancies in order to further both basic research in oncology and the implementation of precision treatments in the clinic.

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Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression

Cited by 20 publications

References 94 publications

Integrated enhancer regulatory network by enhancer–promoter looping in gastric cancer

Integrated enhancer regulatory network by enhancer–promoter looping in gastric cancer

Revealing the pathogenesis of gastric intestinal metaplasia based on the mucosoid air-liquid interface

Spatial Dissection of the Immune Landscape of Solid Tumors to Advance Precision Medicine

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