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| Open AccessRobustly federated learning model for identifying high-risk patients with postoperative gastric cancer recurrence
Medical data faces isolation and cross-center performance issues. Here, the authors propose a robust federated learning model to identify high-risk postoperative gastric cancer recurrence, achieving promising results across data from four independent medical institutions.
- Bao Feng
- , Jiangfeng Shi
- & Wansheng Long
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Article
| Open AccessNeoadjuvant camrelizumab and apatinib combined with chemotherapy versus chemotherapy alone for locally advanced gastric cancer: a multicenter randomized phase 2 trial
Neoadjuvant treatment represents a therapeutic option for locally advanced gastric cancer (LAGC). Here the authors report the results of a randomized phase 2 trial of camrelizumab (anti-PD1) and apatinib (anti-VEGFR2) combined with nab-paclitaxel plus S-1 versus chemotherapy alone as neoadjuvant treatment for LAGC.
- Jian-Xian Lin
- , Yi-Hui Tang
- & Chang-Ming Huang
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Article
| Open AccessLncRNA MIR200CHG inhibits EMT in gastric cancer by stabilizing miR-200c from target-directed miRNA degradation
The roles of long non-coding RNAs (lncRNAs) in different subtypes of gastric cancer (GC) remain to be characterized. Here, the authors identify lncRNA MIR200CHG as a master regulator of Microsatellite stable (MSS)/epithelial-mesenchymal transition (EMT) GC subtype, which inhibits EMT and metastasis by stabilizing miR-200c.
- Yixiao Zhu
- , Chengmei Huang
- & Xin Wang
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Article
| Open AccessIndocyanine green fluorescence imaging-guided versus conventional laparoscopic lymphadenectomy for gastric cancer: long-term outcomes of a phase 3 randomised clinical trial
Due to high rate of metastasis, lymphadenectomy is a cornerstone of the surgical treatment of gastric cancer however the accurate dissection of lymph nodes (LN) can be challenging. Here, the authors present the long-term outcomes of a randomised control trial investigating indocyanine green fluorescence image-guided LN retrieval in gastric cancer patients undergoing laparoscopic gastrectomy.
- Qi-Yue Chen
- , Qing Zhong
- & Chang-Ming Huang
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Article
| Open AccessA tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development
Within gastrointestinal tissues, tuft cells, a rare population of chemo-sensory epithelial cells, can promote the activation of type 2 innate lymphoid cells (ILC2s). Here the authors show that tuft cells and ILC2s are increased during gastric cancer development and that the pharmacologic inhibition of tuft cell derived IL25 or ILC2-produced IL13 reduces gastric tumor growth.
- Ryan N. O’Keefe
- , Annalisa L. E. Carli
- & Michael Buchert
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Article
| Open AccessLactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer
Cuproptosis regulation in tumors is unclear. Here the authors find that copper promotes METTL16 lactylation, inducing cuproptosis via stabilizing FDX1 in gastric cancer. Targeting lactyl-METTL16 and cuproptosis offers a potential feasible strategy for cancer therapy.
- Lianhui Sun
- , Yuan Zhang
- & Chen Huang
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Article
| Open AccessBiology-guided deep learning predicts prognosis and cancer immunotherapy response
The clinical application of data-driven deep learning models remains challenging. Here, a biology-guided deep learning approach allows the simultaneous prediction of the tumour immune and stromal microenvironment status as well as treatment outcomes from medical images in gastric cancer.
- Yuming Jiang
- , Zhicheng Zhang
- & Ruijiang Li
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Article
| Open AccessNeoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial
Neoadjuvant chemotherapy followed by gastrectomy is considered standard of care for locally advanced gastric and gastroesophageal junction (G/GEJ) cancers. Here the authors report the results of a phase 2 trial of neoadjuvant sintilimab (anti-PD1) plus chemoradiotherapy in patients with locally advanced G/GEJ tumors.
- Jia Wei
- , Xiaofeng Lu
- & Baorui Liu
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Article
| Open AccessOncogenic structural aberration landscape in gastric cancer genomes
Gastric cancers (GC) are driven by genomic alterations, but the underlying molecular mechanisms remain unclear. Here, the authors analyse the structural rearrangement landscape of 170 GCs using whole-genome sequencing, identify recurrent structural variant hotspots and find oncogene amplicons driven by extrachromosomal DNA.
- Mihoko Saito-Adachi
- , Natsuko Hama
- & Tatsuhiro Shibata
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Article
| Open AccessSingle-cell analysis of gastric signet ring cell carcinoma reveals cytological and immune microenvironment features
The tumour microenvironment in signet ring cell carcinoma (SRCC) remains to be characterised. Here, the authors perform single-cell RNA sequencing and reveal distinct features compared to moderately/poorly differentiated adenocarcinoma.
- Weizhu Zhao
- , Yanfei Jia
- & Jie Chai
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Article
| Open AccessHyperphosphorylated PTEN exerts oncogenic properties
PTEN has tumor suppressive functions. Here the authors report that PTEN C-tail hyperphosphorylation promotes neoplastic growth through oncogenic activation of WNT signalling.
- Janine H. van Ree
- , Karthik B. Jeganathan
- & Jan M. van Deursen
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Article
| Open AccessADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer
Resistance to 5-fluorouracil and cisplatin (5FU + CDDP) presents a major issue in patients with gastric cancer. Here, the authors establish 5FU + CDDP resistant intestinal gastric cancer patient-derived organoids and identify JAK/STAT-ADAR1 altered lipid metabolism as a regulator of chemoresistance.
- Tin-Lok Wong
- , Jia-Jian Loh
- & Stephanie Ma
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Article
| Open AccessSingle-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis
Peritoneal metastasis is one of the most common forms of death for gastrointestinal cancers, however, its cell composition is incompletely understood. Here, the authors use single cell RNA-seq of peritoneal metastases from 35 patients and show diversity in immune cells, and plasticity in cancer cell phenotypes and autophagy related genes as biomarkers of prognosis.
- Xuan-Zhang Huang
- , Min-Jiao Pang
- & Zhen-Ning Wang
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Article
| Open AccessMultilevel proteomic analyses reveal molecular diversity between diffuse-type and intestinal-type gastric cancer
The molecular differences between the two major gastric cancer subtypes diffuse-type gastric cancer (DGC) and intestinaltype gastric cancer (IGC) remain to be investigated. Here, integrated analysis of proteome, phospho-proteome and transcription factor activity for DGC and IGC reveals potential subtypes.
- Wenhao Shi
- , Yushen Wang
- & Chen Ding
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Article
| Open AccessNeoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer
Immune checkpoint inhibitors and antiangiogenic agents have shown some activity in patients with late-stage gastric cancer. Here the authors report the results of a phase II trial of neoadjuvant anti-PD1 (camrelizumab), antiangiogenic agent (apatinib), and chemotherapy (S-1 ± Oxaliplatin) in stage T4a/bN + M0 gastric cancer patients.
- Song Li
- , Wenbin Yu
- & Lian Liu
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Article
| Open AccessPrognostic and predictive value of a pathomics signature in gastric cancer
The current tumour-node-metastasis staging system alone cannot provide adequate information for prognosis and adjuvant chemotherapy benefits in patients with gastric cancer. Herein, the authors propose a pathomics signature that was derived from multiple features of haematoxylin and eosin-stained slides.
- Dexin Chen
- , Meiting Fu
- & Jun Yan
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Article
| Open AccessThe Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction
Surgery is an important part of treatment for gastric adenocarcinoma, however, the consensus on perioperative care is less clear. Here, the authors report the results of a phase II clinical trial investigating neoadjuvant camrelizumab with concurrent chemoradiotherapy, followed by surgery for the treatment of advanced gastric adenocarcinoma.
- Zhaoqing Tang
- , Yan Wang
- & Yihong Sun
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Article
| Open AccessESRP1-regulated isoform switching of LRRFIP2 determines metastasis of gastric cancer
ESRP1 is reported to regulate the alternative splicing of some genes involved in epithelial–mesenchymal transition. Here the authors show that LRRFIP2 is a target of ESRP1 and that two spliced variants of LRRFIP2 have opposing functions in gastric cancer metastasis
- Jihee Lee
- , Kyoungwha Pang
- & Seong-Jin Kim
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Article
| Open AccessA single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer
In patients with advanced gastric cancer (AGC), resistance to treatment with trastuzumab and cytotoxic chemotherapy remains high. Here, the authors report the results of a phase Ib/II clinical trial assessing the safety and clinical response to a quadruplet regimen of pembrolizumab, trastuzumab, capecitabine, and cisplatin as a first-line therapy for HER2-positive AGC.
- Choong-kun Lee
- , Sun Young Rha
- & Hyun Cheol Chung
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Article
| Open AccessProteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies
The mechanisms of resistance to therapy in gastric cancer remain to be explored. Here, proteomic profiling of 206 tumour tissues from patients treated with chemotherapy and anti-HER2-based therapy results in the identification of four molecular subtypes and the development of prognostic models.
- Yan Li
- , Chen Xu
- & Chen Ding
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| Open AccessPangenomic analysis of Chinese gastric cancer
Human pan-genomics are increasing our knowledge of genomic diversity and genetic factors in disease. Here, the authors built a gastric cancer pan-genome that included the sequences of Chinese Han patients, and predicted putative and previously unaligned genes associated with gastric cancer.
- Yingyan Yu
- , Zhen Zhang
- & Zhenggang Zhu
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Article
| Open AccessNoninvasive imaging of the tumor immune microenvironment correlates with response to immunotherapy in gastric cancer
Tumour microenvironment has been linked with immunotherapy response in gastric cancer. Here, the authors use CT-based radiomics to predict neutrophils-to-lymphocyte ratio and response to immunotherapy.
- Weicai Huang
- , Yuming Jiang
- & Guoxin Li
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Article
| Open AccessscRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory
Gastric cancer can vary in tumour stage and immune cell involvement. Here the authors compare gene expression in immune cell types from the blood and the tumour site from GC patients using single cell and TCR sequencing and show that IL17+CD8+ T cells have a phenotype related to that seen with exhausted cells.
- Keyong Sun
- , Runda Xu
- & Xun Lan
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Article
| Open AccessPredicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment
Predictive methods for gastric cancer to try and differentiate between potential treatment response are required. Here the authors use a multiplexed immunohistochemistry method to propose the proximity of tumour infiltrating immune cells as an indicator of likely therapeutic response.
- Yang Chen
- , Keren Jia
- & Lin Shen
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Article
| Open AccessInstant diagnosis of gastroscopic biopsy via deep-learned single-shot femtosecond stimulated Raman histology
Diagnosis of gastric cancer currently requires gastroscopic biopsy, which requires time and expertize to perform. Here, the authors demonstrate a femto-SRS imaging method which showed high accuracy in diagnosing gastric cancer without the need for pathologistbased diagnosis.
- Zhijie Liu
- , Wei Su
- & Minbiao Ji
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Article
| Open AccessNetwork-based machine learning approach to predict immunotherapy response in cancer patients
Identifying biomarkers for response to immunotherapy in cancer remains challenging. Here, the authors develop an approach based on network biology and machine learning -NetBio- to identify molecular biomarkers of response to immunotherapy across different cancer types and cohorts.
- JungHo Kong
- , Doyeon Ha
- & Sanguk Kim
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Article
| Open AccessDeep neural network trained on gigapixel images improves lymph node metastasis detection in clinical settings
The pathological identification of lymph node metastasis in whole-slide images is demanding and tedious. Here, the authors design an artificial-intelligence-assisted assessment workflow to facilitate the routine counting of metastatic LNs.
- Shih-Chiang Huang
- , Chi-Chung Chen
- & Tse-Ching Chen
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Article
| Open AccessA deep learning model and human-machine fusion for prediction of EBV-associated gastric cancer from histopathology
Epstein–Barr virus-associated gastric cancer shows a robust response to immune checkpoint inhibitors. Here the authors introduce a deep convolutional neural network and its fusion with pathologists for predicting it from histopathology.
- Xueyi Zheng
- , Ruixuan Wang
- & Muyan Cai
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Article
| Open AccessDevelopment and validation of a prognostic and predictive 32-gene signature for gastric cancer
The ability to predict the survival and response to treatment of cancer patients may improve patient care. Here, the authors generate a 32 gene signature that can predict the survival and response to treatment in gastric cancer patients.
- Jae-Ho Cheong
- , Sam C. Wang
- & Tae Hyun Hwang
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Article
| Open AccessThree-year outcomes of the randomized phase III SEIPLUS trial of extensive intraoperative peritoneal lavage for locally advanced gastric cancer
Extensive intraoperative peritoneal lavage (EIPL) has been proposed as an approach to reduce peritoneal metastasis in patients with locally advanced gastric cancer undergoing gastrectomy. Here the authors report the results of the multicentric phase III SEIPLUS trial, showing that EIPL does not improve 3-year survival rate in patients with advanced gastric cancer.
- Jing Guo
- , Aman Xu
- & Dazhi Xu
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Article
| Open AccessFocal amplifications are associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma
The role of focal amplifications and extrachromosomal DNA (ecDNA) is unknown in gastric cardia adenocarcinoma (GCA). Here, the authors identify frequent focal amplifications and ecDNAs in Chinese GCA patient samples, as well as the potential associations of these alterations with prognosis and dietary habits.
- Xue-Ke Zhao
- , Pengwei Xing
- & Li-Dong Wang
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Article
| Open AccessWhole-exome sequencing of alpha-fetoprotein producing gastric carcinoma reveals genomic profile and therapeutic targets
Alpha-fetoprotein producing gastric carcinomas (AFPGC) are rare and aggressive. Here, the authors profile AFPGC tumours using whole exome sequencing, and find amplifications in CCNE1 and ERBB2 that are associated with poor outcomes but are potential therapeutic targets, as shown in patient-derived xenografts.
- Jun Lu
- , Yongfeng Ding
- & Lisong Teng
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Article
| Open AccessIntratumoral CXCR5+CD8+T associates with favorable clinical outcomes and immunogenic contexture in gastric cancer
The prognostic value of tumor infiltrating lymphocytes in gastric cancer remains controversial. Here the authors show a consistent association between higher density of intratumoral CXCR5+CD8+ T cells and longer overall survival in four different cohorts of patients with gastric cancer.
- Jieti Wang
- , Ruochen Li
- & Hua Huang
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Article
| Open AccessChromatin accessibility of circulating CD8+ T cells predicts treatment response to PD-1 blockade in patients with gastric cancer
Anti-PD-1 therapy could induce a durable response in patients with gastric cancer, however biomarkers to predict response to immunotherapy are generally lacking. Here the authors report that openness of chromatin in circulating CD8+ T cells predicts treatment outcome in patients with metastatic gastric cancer treated with pembrolizumab.
- Hyun Mu Shin
- , Gwanghun Kim
- & Hang-Rae Kim
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Article
| Open AccessNeoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer
Neoadjuvant FLOT regimen has shown promising results for the treatment of locally advanced gastric cancer, however SOX regimen remains the preferred chemotherapy in Eastern countries. Here the authors report that the two therapies result in similar outcomes, measured as clinical downstaging and pathological response, in a phase II randomized clinical trial.
- Birendra Kumar Sah
- , Benyan Zhang
- & Zhenggang Zhu
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Article
| Open AccessClinically applicable histopathological diagnosis system for gastric cancer detection using deep learning
The early detection and accurate histopathological diagnosis of gastric cancer are essential factors that can help increase the chances of successful treatment. Here, the authors report on a digital pathology tool achieving high performance on a real world test dataset and show that the system can aid pathologists in improving diagnostic accuracy.
- Zhigang Song
- , Shuangmei Zou
- & Huaiyin Shi
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Article
| Open AccessWhite blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer
Identifying patients that will respond to a particular therapy remains a key challenge in precision oncology. Here, in gastric cancer, the authors show that circulating tumour DNA can predict recurrence, provided that the signal from white blood cells is filtered out.
- Alessandro Leal
- , Nicole C. T. van Grieken
- & Victor E. Velculescu
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Article
| Open AccessGastric squamous-columnar junction contains a large pool of cancer-prone immature osteopontin responsive Lgr5−CD44+ cells
Cancers arising from the gastric squamous-columnar junction have high incidence and are characterized by a poor prognosis. Here, the authors use genetic mouse models to show that loss of p53 and Rb1 expression results in preferential tumour development at the gastric squamous-columnar junction that contains a large pool of osteopontin responsive Lgr5-CD44+ cells.
- Dah-Jiun Fu
- , Lianghai Wang
- & Alexander Yu. Nikitin
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Article
| Open AccessMacrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry
Tumor associated macrophages are functionally and phenotypically heterogeneous. Here the authors describe the spatial distribution of distinct macrophage populations within regions of gastric cancer and probe their associations with clinical outcomes, gene signatures and PDL1 expression.
- Yu-Kuan Huang
- , Minyu Wang
- & Alex Boussioutas
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| Open AccessMicroenvironment meets lineage complexity in junctional tumorigenesis
Using a sensitizing genetic model, Moon and colleagues provide compelling data for a determinant role of microenvironment in tumorigenesis, and lend support to the notion that such influences can be pharmacologically dampened to reduce the onset of cancers.
- Wa Xian
- & Frank McKeon
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Article
| Open AccessIL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization
Mast cells within the tumor microenvironment have controversial roles. Here, the authors show, using genetic mouse models, that in gastric cancer, mast cells at the periphery of the tumors are activated via cancer cell produced-IL33 and promote tumorigenesis by recruiting macrophages within the tumors.
- Moritz F. Eissmann
- , Christine Dijkstra
- & Matthias Ernst
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Article
| Open AccessKrt5+/Krt15+ foregut basal progenitors give rise to cyclooxygenase-2-dependent tumours in response to gastric acid stress
Cellular extrinsic environmental factors contribute to tumour development. Here, the authors show that gastric acid stress stimulates tumour formation from a defined tumour-competent Krt5 + /Krt15 + foregut basal progenitor cell population.
- Hyeongsun Moon
- , Jerry Zhu
- & Andrew C. White
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Article
| Open AccessA region-resolved mucosa proteome of the human stomach
The human stomach is divided into seven anatomically distinct regions but their protein composition is largely unknown. Here, the authors present a region-resolved map of the healthy human stomach mucosa as well as mucosa proteomes of tumor and tumor nearby tissue from gastric cancer patients.
- Xiaotian Ni
- , Zhaoli Tan
- & Jun Qin
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Article
| Open AccessA time-resolved multi-omic atlas of the developing mouse stomach
The mammalian stomach is a complex organ with diverse roles in health and disease. Here, the authors integrate proteomics and transcriptomics to analyze the mouse stomach at 15 time points during development, providing molecular level insights into system-wide developmental changes.
- Xianju Li
- , Chunchao Zhang
- & Jun Qin
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Article
| Open AccessRhoGAP domain-containing fusions and PPAPDC1A fusions are recurrent and prognostic in diffuse gastric cancer
Diffuse Gastric Cancer (DGC) is increasingly being considered separate to intestinal type gastric cancer; several fusions events have been reported as drivers of the disease but few of those have been subsequently validated. Here the authors perform RNA-seq on early-onset DGC patients who had not been treated with chemotherapy or radiation and identify a previously unknown fusion.
- Hanna Yang
- , Dongwan Hong
- & Hark Kyun Kim
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Article
| Open AccessSCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis
Upstream pathways regulating Brg1 stability and their role in carcinogenesis are unknown. Here they show Brg1 to be phosphorylated by CK1δ to promote its ubiquitination by SCFFBW7 (FBW7), Brg1 stabilization to promote gastric cancer metastasis, and suggest targeting Brg1 in FBW7 compromised gastric cancer.
- Li-Yu Huang
- , Junjie Zhao
- & Wenyi Wei
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Article
| Open AccessImmunomodulatory role of Keratin 76 in oral and gastric cancer
Keratin 76 (Krt76) is an epithelial differentiation marker that is downregulated in oral squamous cell carcinomas, correlating with poor prognosis. Here the authors show that genetic ablation of Krt76 in a mouse model results in increased susceptibility to carcinogenesis via enhanced accumulation of Tregs.
- Inês Sequeira
- , Joana F. Neves
- & Fiona M. Watt
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Article
| Open AccessPrognostic significance of frequent CLDN18-ARHGAP26/6 fusion in gastric signet-ring cell cancer
Signet-ring cell carcinoma (SRCC) is a unique type of gastric cancer with no prognostic features. Here, the authors report a CLDN18-ARHGAP26/6 gene fusion in patients with a high signet-ring cell content, poor survival outcomes, and who experience no benefit from platinum/fluoropyrimidines-based chemotherapy.
- Yang Shu
- , Weihan Zhang
- & Jiankun Hu
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Article
| Open AccessEstrogen-related receptor gamma functions as a tumor suppressor in gastric cancer
Very little is known regarding the molecular mechanisms involved in gastric cancer development. Here the authors show estrogen-related receptor gamma (ESRRG) is a tumor suppressor in gastric cancer and suggest the mechanism of this tumor suppression function involves the inhibition of Wnt signaling.
- Myoung-Hee Kang
- , Hyunji Choi
- & Yun-Yong Park