Chi-Lee C. Ho, Michael B. Gilbert, Guillaume Urtecho, Hyoungjoo Lee, David A. Drew, Samuel J. Klempner, Jin S. Cho, Thomas J. Ryan, Naryan Rustgi, Hyuk Lee, Jeeyun Lee, Alexander Caraballo, Marina V. Magicheva-Gupta, Carmen Rios, Alice E. Shin, Yuen-Yi Tseng, Jeremy L. Davis, Daniel C. Chung, Andrew T. Chan, Harris H. Wang, Sandra Ryeom
{"title":"Stool protein mass spectrometry identifies biomarkers for the early detection of diffuse-type gastric cancer","authors":"Chi-Lee C. Ho, Michael B. Gilbert, Guillaume Urtecho, Hyoungjoo Lee, David A. Drew, Samuel J. Klempner, Jin S. Cho, Thomas J. Ryan, Naryan Rustgi, Hyuk Lee, Jeeyun Lee, Alexander Caraballo, Marina V. Magicheva-Gupta, Carmen Rios, Alice E. Shin, Yuen-Yi Tseng, Jeremy L. Davis, Daniel C. Chung, Andrew T. Chan, Harris H. Wang, Sandra Ryeom","doi":"10.1158/1940-6207.capr-23-0449","DOIUrl":null,"url":null,"abstract":"There is a high unmet need for early detection approaches for diffuse gastric cancer (DGC). We examined whether the stool proteome of mouse models of GC or individuals with hereditary diffuse GC (HDGC) have utility as biomarkers for early detection. Proteomic mass spectrometry of stool from a genetically engineered mouse model driven by oncogenic KrasG12D and loss of p53 and Cdh1 in gastric parietal cells (known as TCON mice) identified differentially abundant proteins compared to littermate controls. Immunoblot assays validated a panel of proteins including actinin alpha 4 (ACTN4), N-acylsphingosine amidohydrolase 2 (ASAH2), dipeptidyl peptidase 4 (DPP4), and valosin-containing protein (VCP) as enriched in TCON stool compared to littermate control stool. Immunofluorescence analysis of these proteins in TCON stomach sections revealed increased protein expression as compared to littermate controls. Proteomic mass spectrometry of stool obtained from HDGC patients with CDH1 mutations identified increased expression of ASAH2, DPP4, VCP, lactotransferrin (LTF), and tropomyosin-2 (TPM2) relative to stool from healthy sex and age-matched donors. Chemical inhibition of ASAH2 using C6-urea ceramide was toxic to GC cell lines and patient derived-GC organoids. This toxicity was reversed by adding downstream products of the S1P synthesis pathway, suggesting a dependency on ASAH2 activity in GC. An exploratory analysis of the HDGC stool microbiome identified features which correlated with patient tumors. Here we provide evidence supporting the potential of analyzing stool biomarkers for the early detection of DGC.","PeriodicalId":9373,"journal":{"name":"Cancer Prevention Research","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Prevention Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1940-6207.capr-23-0449","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
There is a high unmet need for early detection approaches for diffuse gastric cancer (DGC). We examined whether the stool proteome of mouse models of GC or individuals with hereditary diffuse GC (HDGC) have utility as biomarkers for early detection. Proteomic mass spectrometry of stool from a genetically engineered mouse model driven by oncogenic KrasG12D and loss of p53 and Cdh1 in gastric parietal cells (known as TCON mice) identified differentially abundant proteins compared to littermate controls. Immunoblot assays validated a panel of proteins including actinin alpha 4 (ACTN4), N-acylsphingosine amidohydrolase 2 (ASAH2), dipeptidyl peptidase 4 (DPP4), and valosin-containing protein (VCP) as enriched in TCON stool compared to littermate control stool. Immunofluorescence analysis of these proteins in TCON stomach sections revealed increased protein expression as compared to littermate controls. Proteomic mass spectrometry of stool obtained from HDGC patients with CDH1 mutations identified increased expression of ASAH2, DPP4, VCP, lactotransferrin (LTF), and tropomyosin-2 (TPM2) relative to stool from healthy sex and age-matched donors. Chemical inhibition of ASAH2 using C6-urea ceramide was toxic to GC cell lines and patient derived-GC organoids. This toxicity was reversed by adding downstream products of the S1P synthesis pathway, suggesting a dependency on ASAH2 activity in GC. An exploratory analysis of the HDGC stool microbiome identified features which correlated with patient tumors. Here we provide evidence supporting the potential of analyzing stool biomarkers for the early detection of DGC.
期刊介绍:
Cancer Prevention Research publishes original studies, reviews, and perspectives in the field of cancer prevention. Its scope includes the molecular and cellular biology of premalignancy and early lesions; genetic and environmental risk factors; risk assessment and reduction; early detection research (cancer screening and diagnosis); and preventive interventions (chemoprevention, immunoprevention, and others) to intercept cancer development at early stages prior to initiation, promotion, or progression. The journal comprises preclinical, clinical, and translational research, with special attention given to molecular discoveries and an emphasis on building a translational bridge between the basic and clinical sciences.