Wenchen Gong

Tianjin Medical University Cancer Institute and Hospital

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Bin Meng

Tianjin Medical University Cancer Institute and Hospital

Huilai Zhang

Tianjin Medical University Cancer Institute and Hospital

Lanfang Li

Tianjin Medical University Cancer Institute and Hospital

Lihua Qiu

Tianjin Medical University Cancer Institute and Hospital

Xianhuo Wang

Tianjin Medical University Cancer Institute and Hospital

Shiyong Zhou

Tianjin Medical University Cancer Institute and Hospital

Xiubao Ren

Tianjin Medical University Cancer Institute and Hospital

Hua Guo

Chinese Academy of Medical Sciences & Peking Union Medical College

Yuchao He

Tianjin Medical University Cancer Institute and Hospital

Tingting Zhang

Xijing Hospital

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Tianjin Medical University Cancer Institute and Hospital

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Tianjin Medical University

National Clinical Research

Peking University

Tianjin Medical University General Hospital

Sun Yat-sen University

Chinese Academy of Sciences

Capital Medical University

Chinese Academy of Medical Sciences & Peking Union Medical College

Nanjing Medical University

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CCDC34 maintains stemness phenotype through β-catenin-mediated autophagy and promotes EGFR-TKI resistance in lung adenocarcinoma

Cancer Gene Therapy (2024)

Ping Yue Yuchao He Ran Zuo Wenchen Gong Yu Wang

10.1038/s41417-024-00843-y

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Citations (1)

Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma

International Journal of Biological Sciences (2023)

Jinfang Cui Yuchao He Fuyi Zhu Wenchen Gong Ran Zuo

Cisplatin is a first-line chemotherapy drug for lung adenocarcinoma (LUAD).However, its therapeutic efficacy is limited because of serious side effects and acquired drug resistance.Targeting HER2 has been proven to be a viable therapeutic strategy against LUAD.Moreover, inetetamab, an innovative anti-HER2 monoclonal antibody, has a more potent antibody-dependent cell-mediated cytotoxicity (ADCC)-inducing effect than trastuzumab, which has been shown to be an effective and rational strategy in the clinic when combined with multiple chemotherapeutic agents.Thus, the present study aimed to explore the synergistic effects of cisplatin (DDP) and inetetamab in LUAD cells and investigate the detailed underlying mechanisms.Here, in vitro and in vivo, we found that the combination of inetetamab and cisplatin induced synergistic effects, including induction of pyroptosis, in LUAD.Mechanistic studies revealed that inetetamab combined with cisplatin inhibited HER2/AKT/Nrf2 signaling to increase ROS levels, which triggered NLRP3/caspase-1/GSDMB-mediated pyroptosis to synergistically enhance antitumor efficacy in LUAD cells.In addition, cisplatin enhanced the PBMC-killing ability of inetetamab by inducing GSDMB-mediated pyroptosis, which can be explained by increased secretion of IFN-γ.Our study reveals that the anti-HER2 monoclonal antibody inetetamab may be an attractive candidate for LUAD therapy, which opens new avenues for therapeutic interventions for LUAD.

Pyroptosis

10.7150/ijbs.82980

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Citations (11)

The Combination of R848 with Sorafenib Enhances Antitumor Effects by Reprogramming the Tumor Immune Microenvironment and Facilitating Vascular Normalization in Hepatocellular Carcinoma

Advanced Science (2023)

Yuchao He Linlin Zhan Jian Shi Man‐Yu Xiao Ran Zuo

Novel promising strategies for combination with sorafenib are urgently needed to enhance its clinical benefit and overcome toxicity in hepatocellular carcinoma (HCC). the molecular and immunomodulatory antitumor effects of sorafenib alone and in combination with the new immunotherapeutic agent R848 are presented. Syngeneic HCC mouse model is presented to explore the antitumor effect and safety of three sorafenib doses alone, R848 alone, or their combination in vivo. R848 significantly enhances the sorafenib antitumor activity at a low subclinical dose with no obvious toxic side effects. Furthermore, the combination therapy reprograms the tumor immune microenvironment by increasing antitumor macrophages and neutrophils and preventing immunosuppressive signaling. Combination treatment promotes classical M1 macrophage-to-FTH1high M1 macrophage transition. The close interaction between neutrophils/classical M1 macrophages and dendritic cells promotes tumor antigen presentation to T cells, inducing cytotoxic CD8+ T cell-mediated antitumor immunity. Additionally, low-dose sorafenib, alone or combined with R848, normalizes the tumor vasculature, generating a positive feedback loop to support the antitumor immune environment. Therefore, the combination therapy reprograms the HCC immune microenvironment and normalizes the vasculature, improving the therapeutic benefit of low-dose sorafenib and minimizing toxicity, suggesting a promising novel immunotherapy (R848) and targeted therapy (tyrosine kinase inhibitors) combination strategy for HCC treatment.

Combination therapy

10.1002/advs.202207650

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Citations (17)

Integrative genomic and transcriptomic analysis reveals genetic alterations associated with the early progression of follicular lymphoma

British Journal of Haematology (2023)

Fenghua Gao Hengqi Liu Xiangrui Meng Chun‐Feng Liu Jiesong Wang

Follicular lymphoma (FL), the most common indolent lymphoma, is a clinically and genetically heterogeneous disease. However, the prognostic value of driver gene mutations and copy number alterations has not been systematically assessed. Here, we analysed the clinical-biological features of 415 FL patients to identify variables associated with disease progression within 24 months of first-line therapy (POD24). Patients with B symptoms, elevated lactate dehydrogenase and β2-microglobulin levels, unfavourable baseline haemoglobin levels, advanced stage, and high-risk FL International Prognostic Index (FLIPI) scores had an increased risk of POD24, with FLIPI being the most important factor in logistic regression. HIST1H1D, identified as a driver mutation, was correlated with POD24. Gains of 6p22.2 (HIST1H1D) and 18q21.33 (BCL2) and loss of 1p36.13 (NBPF1) predicted POD24 independent of FLIPI. Gene expression profiling of FL samples showed that the POD24 cohort was significantly enriched in the inflammatory response (mediated by interferon and tumour necrosis factor), cell cycle regulation (transcription, replication and proliferation) sets and PI3K-AKT-mTOR signalling. This result was further validated with transcriptome-wide information provided by RNA-seq at single-cell resolution. Our study, performed on a large cohort of FL patients, highlights the importance of distinctive genetic alterations and gene expression relevant to disease diagnosis and early progression.

Follicular lymphoma

International Prognostic Index

10.1111/bjh.18974

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Citations (8)

OVOL2 induces autophagy-mediated epithelial-mesenchymal transition by the ERK1/2 MAPK signaling in lung adenocarcinoma

iScience (2024)

Yali Wang Lin Shi Yuchao He Wenchen Gong Yanyan Cui

Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related death worldwide. Epithelial-mesenchymal transition (EMT) plays an important role in malignant tumor progression. Recently, accumulating evidence has shown that autophagy is involved in the regulation of EMT-induced migration. Therefore, the exploration of targets to inhibit EMT by targeting autophagy is important. In this study, we found that OVO-like zinc finger 2 (OVOL2) may be a key target for regulating autophagy-induced EMT. Firstly, we found that OVOL2 expression was dramatically downregulated in LUAD. Low expression of OVOL2 is an indicator of poor prognosis in LUAD.

10.1016/j.isci.2024.108873

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Genetic characteristics involving the PD-1/PD-L1/L2 and CD73/A2aR axes and the immunosuppressive microenvironment in DLBCL

Journal for ImmunoTherapy of Cancer (2022)

Tingting Zhang Hengqi Liu Lei Jiao Zhenzhen Zhang Jin He

Background Targeting the PD-1/PD-L1/L2 (programmed cell death protein 1/programmed cell death ligand 1/ligand 2) pathway combined with other immunosuppressive signalings, such as CD73/A2aR (A2a adenosine receptor) adenosine signaling, has emerged as a promising strategy for cancer treatment. The genetic characteristics of these immune checkpoints need to be further investigated in diffuse large B-cell lymphoma (DLBCL). Methods We performed whole-exome sequencing/targeted deep sequencing to investigate the genetic characteristics of PD-1/PD-L1/L2 and CD73/A2aR. The immunosuppressive effect of these two pathways on the tumor microenvironment was evaluated via RNA sequencing. Single-cell RNA sequencing was further applied to investigate the dysfunctional CD8+ T cells. In addition, multiplex immunofluorescence staining was used to quantitatively assess the expression of dysfunctional CD8 + T cells in DLBCL. Results SP140 was identified as a novel translocation partner for PD-L1, and a new inversion was detected between PD-L1 and PD-L2, both leading to the upregulation of PD-L1 expression. CD73 genetic mutations did not increase mRNA and protein expression. Patients with genetically altered CD73 tended to have a better overall survival than patients with wild-type CD73. Both PD-1/PD-L1 and CD73/A2aR signaling mediated the immunosuppressive microenvironment in DLBCL. The numbers of CD8 + T cells with PD-1 and A2aR expression were positively correlated with the number of dysfunctional CD8 + T cells (R 2 =0.974, p = 0.013). According to the grades of dysfunctional CD8 + T cells we defined, grade 1 dysfunctional CD8 + T cells, with either PD-1 + or A2aR + , were significantly associated with poorer survival than grade 0 dysfunctional CD8 + T cells, with both PD-1 − and A2aR − ; and patients with grade 2 dysfunctional CD8 + T cells showed the worst clinical outcomes. Conclusions This study describes the additional genetic basis of PD-L1 overexpression and characterizes certain genetic alterations of CD73/A2aR in DLBCL. The degree of T-cell dysfunction is correlated with clinical outcomes. Strategies that reverse T-cell dysfunction by inhibiting PD-1/PD-L1/L2, particularly in combination with CD73/A2aR, may show potential as effective therapeutic options for DLBCL.

10.1136/jitc-2021-004114

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Citations (35)

Expression of epithelial‐mesenchymal transition regulators TWIST, SLUG and SNAIL in follicular thyroid tumours may relate to widely invasive, poorly differentiated and distant metastasis

Histopathology (2018)

Jianghua Wu Yanhui Zhang Run-Fen Cheng Wenchen Gong Tingting Ding

Aims To assess the expression of epithelial–mesenchymal transition ( EMT ) regulators in follicular thyroid tumours. Methods and results The expression of E‐cadherin (E‐ CAD ) and transcription factors TWIST , SLUG and SNAIL in follicular thyroid tumours was examined by immunohistochemistry in tissue samples, including 18 follicular adenomas ( FA ), 12 minimally invasive follicular thyroid carcinomas ( MI ‐ FTC ), 16 widely invasive follicular thyroid carcinomas ( WI ‐ FTC ), 10 poorly differentiated follicular thyroid carcinomas ( PDTC ) and six anaplastic thyroid carcinomas ( ATC ). Metastatic tumour tissues from six of these cases were also examined. The results showed an increasing expression trend of EMT regulators in a panel of follicular tumour cases with a spectrum of morphological subtypes from low‐ to high‐risk malignancy. The expression of EMT regulators was higher in the WI ‐ FTC , PDTC and ATC groups but focal and lower in the FA and MI ‐ FTC groups. Different expression intensity of E‐ CAD and EMT regulators at the tumour centre part and the invasive front ( IF ) was observed. The loss of E‐ CAD and expression of EMT regulators was significantly correlated with distant metastasis and vascular invasion ( VI ) in the well‐differentiated follicular carcinoma ( WD ‐ FTC ), and six tumours of metastatic sites also showed variables positive for EMT regulators. The disease‐free survival analysis showed an apparent relationship between the expression of EMT regulators and the tumour disease‐free outcomes in WD ‐ FTC . Conclusions Our study supported the role of EMT in the development of follicular thyroid carcinoma and indicated that EMT regulatory proteins may play an important role in WD ‐ FTC that are widely invasive and exhibit distant metastasis.

Slug

Follicular thyroid cancer

Twist transcription factor

10.1111/his.13778

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Citations (22)

A novel immune-related epigenetic signature based on the transcriptome for predicting the prognosis and therapeutic response of patients with diffuse large B-cell lymphoma

Clinical Immunology (2022)

Xiaoxuan Wang Yuheng Hong Shen Meng Wenchen Gong Tianyuan Ren

Epigenetic modifications contribute to lymphomagenesis. Here, we performed an expression clustering analysis and identified two epigenetic-related clusters (EC1 and EC2). EC1 presented abundant TP53, MYD88, HIST1H1D, HIST1H1C, KMT2D and EZH2 mutations and an inferior prognosis. Pathways involved in the regulation of DNA methylation/demethylation, histone methyltransferase activity, and protein methyltransferase activity were significantly enriched in EC1. However, EC2 was frequently accompanied by B2M, CD70 and MEF2B mutations, which presented with enrichments in DNA damage repair, cytokine-mediated and B-cell activated immune signaling, increased levels of CD8+ T-, γδT- and T helper-cells, as well as immune scores and immunogenic cell death (ICD) modulators. According to the prediction, EC1 was more sensitive to vorinostat, serdemetan and navitoclax. However, ruxolitinib, cytarabine and CP466722 were more suitable treatments for EC2. The novel immune-related epigenetic signature exhibits promising clinical predictive value for diffuse large B-cell lymphoma (DLBCL), particularly for guiding epigenetic therapeutic regimens. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) based combination treatment regimens are suggested.

Vorinostat

10.1016/j.clim.2022.109105

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Citations (17)

Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes

Cancer Cell (2019)

Ruidong Xue Lu Chen Chong Zhang Masashi Fujita Ruoyan Li

Intrahepatic Cholangiocarcinoma

Laser capture microdissection

Microdissection

Nestin

10.1016/j.ccell.2019.04.007

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Citations (231)

Nodal signaling activates the Smad2/3 pathway to regulate stem cell-like properties in breast cancer cells.

PubMed (2017)

Wenchen Gong Baocun Sun Huizhi Sun Xiulan Zhao Danfang Zhang

Nodal signaling plays several vital roles in the embryogenesis process. However, its reexpression in breast cancer is correlated with cancer progression, metastasis and poor prognosis. Recently, Nodal has also been reported to regulate self-renewal capacity in pancreatic cancer. This study aimed to explore the role of Nodal in breast cancer stem cells (BCSCs) and the underlying mechanisms. Therefore, the immunohistochemistry staining of Nodal in 135 human breast cancer cases was performed to analyzed the relationship of Nodal signaling, clinical outcomes and BCSC marker. And the results showed that high Nodal expression was positively correlated with poor prognosis and BCSC marker expression in breast cancer samples. We further assessed the effects of Nodal in regulating the BCSC properties in breast cancer cell lines and xenografts. Then, SB431542 was administered in vitro and in vivo to explore the function of the Smad2/3 pathway. And we demonstrated that Nodal signaling up-regulated the expression of ALDH1, CD44, CD133, Sox2, Oct4 and Nanog by activating the Smad2/3 pathway, thereby enhancing the tumorigenicity and sphere-forming ability of breast cancer cells. Furthermore, treatment with SB431542 could inhibit the properties of BCSCs in vitro and in vivo. In conclusion, these findings indicate that Nodal signaling may play a vital role in maintaining the BCSC phenotype in breast cancer and serve as a potential target to explore BCSC-specific therapies.

Nodal signaling

Homeobox protein NANOG

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Citations (36)