Proteomics of the Gastric Cancer Response to Chemotherapy Reveals Involvement of the Immune and Metabolic Pathways

Published: 16 Feb 2020 | Version 1 | DOI: 10.17632/bsfcgp927h.1
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Abstract
Chemotherapy is one of the major treatments for gastric cancer (GC), but drug resistance limits the effectiveness of chemotherapy, which results in treatment failure. Here, we investigated the mechanisms of response by profiling the proteome of 206 clinical samples from GC patients undergoing either chemotherapy or anti-HER2 targeted treatment. A total of 12,514 proteins were profiled, and approximately 5,000 proteins were detected in each patient. Consensus clustering revealed four molecular subtypes (G-I to G-IV) based on the proteome patterns, which were represented by metabolism-inositol phosphate, metabolism-glycolysis, immune-TCR signaling, and immune-complement/coagulation. Bioinformatics analysis has revealed that the immune and metabolic pathways serve as the critical axis in response to DOS and XELOX treatment, in which the combination of anti-HER2 targeted treatment can partially diminish the association of the immune and metabolic pathways with the XELOX response. We also developed a prognostic model to predict the chemotherapy response using a logistic regression model based on the proteome (area under the receiver operating characteristic (ROC) curve [AUC] > 0.85). We further elucidated that a GC cell line overexpressing CTSE was sensitive to DOS but not XELOX by increasing the tendency of microtubule stabilization. Altogether, our proteomic analyses provide a comprehensive proteomic resource for understanding the molecular mechanisms of the chemotherapy response in GC and revealed an association between immune or metabolic features and the diverse response to chemotherapy regimens, which can be the basis for the future consultation of therapeutic strategies in the clinic.

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We screened and assembled a whole cohort of 206 GC patients from the Department of Pathology of Zhongshan Hospital, Fudan University (Shanghai, R. P. China). We constructed chemo- and targeted therapy cohorts, namely, the DOS cohort (44 patients treated with DOS), the XELOX cohort (71 patients treated with XELOX) and the HER2 cohort (70 patients who received anti-HER2 therapy), and conducted a comprehensive proteomic analysis of the response of GC to diverse chemotherapies. We aimed to investigate the cellular responses and resistance mechanisms and distinguish between potentially sensitive and resistant individuals based on a specific treatment. Proteomic clustering resulted in four distinct subgroups that showed associations with patient survival, personalized treatment, and clinical outcomes. We found that G-I and G-II were mainly enriched in metabolic pathways, while G-III and G-IV were mainly enriched in immune pathways, and each had different associations with prognosis in diverse ways. Furthermore, we conducted differential proteomic analysis between the chemosensitive group and the chemoresistant group regarding DOS, XELOX, and HER2. Interestingly, we found that in the DOS cohort, the overrepresented proteins in the chemosensitive group were enriched in immune pathways, and the overrepresented proteins in the chemoresistant group were enriched in metabolic pathways. Conversely, in the XELOX cohort, the chemosensitive group was featured by metabolic pathways, and the chemoresistant group was dominated in immune pathways. Conversely, in the XELOX cohort, the overrepresented proteins in the chemosensitive group was enriched in metabolic pathways, and the overrepresented proteins in the chemoresistant group was enriched in immune pathways. In addition, the combination of XELOX with anti-HER2 treatment could partially relieve the immune pathway related to XELOX resistance, showing that the combination therapy might be superior to the single chemotherapy. Finally, independent risk factors among proteins were screened by multivariable logistic regression analysis. Moreover, predictive models for the chemotherapy response were built, with an area under the receiver operating characteristic (ROC) curve (AUC) > 0.85. This study may help clinicians develop an individualized course of treatment for GC patients with distinct features.

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Latest version

  • Version 1

    2020-02-16

    Published: 2020-02-16

    DOI: 10.17632/bsfcgp927h.1

    Cite this dataset

    Li, Yan; Xu, Chen; Wang, Bing; Feng, Jinwen; Tian, Sha; Wang, Yunzhi; Liu, Yang; Qin, Zhaoyu; Jiang, Dongxian; Liu, Yalan; Qin, Jing; Shen, Kuntang; Liu, Tianshu; Wu, Xiaohui; Song, Qi; Zhang, Xiaolei; Sujie, Akesu; Huang, Jie; Sun, Yihong; Hou, Yingyong; Ding, Chen (2020), “Proteomics of the Gastric Cancer Response to Chemotherapy Reveals Involvement of the Immune and Metabolic Pathways”, Mendeley Data, v1 http://dx.doi.org/10.17632/bsfcgp927h.1

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Institutions

Henan Normal University, Zhongshan Hospital Fudan University, Fudan University

Categories

Proteomics, Chemotherapy, Stomach Cancer

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