Oncotarget

Research Papers:

Direct molecular dissection of tumor parenchyma from tumor stroma in tumor xenograft using mass spectrometry-based glycoproteomics

Xiaoying Ye, Brian T. Luke, Bih-Rong Wei, Jan A. Kaczmarczyk, Jadranka Loncarek, Jennifer E. Dwyer, Donald J. Johann, Richard G. Saul, Dwight V. Nissley, Frank McCormick, Gordon R. Whiteley and Josip Blonder _

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Oncotarget. 2018; 9:26431-26452. https://doi.org/10.18632/oncotarget.25449

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Abstract

Xiaoying Ye1, Brian T. Luke2, Bih-Rong Wei3, Jan A. Kaczmarczyk4, Jadranka Loncarek5, Jennifer E. Dwyer3, Donald J. Johann6, Richard G. Saul4, Dwight V. Nissley1, Frank McCormick7, Gordon R. Whiteley1 and Josip Blonder1

1National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA

2Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA

3Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA

4Cancer Research Technology Program, Antibody Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA

5Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA

6Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72209, USA

7UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA

Correspondence to:

Josip Blonder, email: blonderj@mail.nih.gov

Keywords: lung cancer; tumor microenvironment

Received: March 22, 2018    Accepted: May 02, 2018    Published: May 29, 2018

ABSTRACT

The most widely used cancer animal model is the human-murine tumor xenograft. Unbiased molecular dissection of tumor parenchyma versus stroma in human-murine xenografts is critical for elucidating dysregulated protein networks/pathways and developing therapeutics that may target these two functionally codependent compartments. Although antibody-reliant technologies (e.g., immunohistochemistry, imaging mass cytometry) are capable of distinguishing tumor-proper versus stromal proteins, the breadth or extent of targets is limited. Here, we report an antibody-free targeted cross-species glycoproteomic (TCSG) approach that enables direct dissection of human tumor parenchyma from murine tumor stroma at the molecular/protein level in tumor xenografts at a selectivity rate presently unattainable by other means. This approach was used to segment/dissect and obtain the protein complement phenotype of the tumor stroma and parenchyma of the metastatic human lung adenocarcinoma A549 xenograft, with no need for tissue microdissection prior to mass-spectrometry analysis. An extensive molecular map of the tumor proper and the associated microenvironment was generated along with the top functional N-glycosylated protein networks enriched in each compartment. Importantly, immunohistochemistry-based cross-validation of selected parenchymal and stromal targets applied on human tissue samples of lung adenocarcinoma and normal adjacent tissue is indicative of a noteworthy translational capacity for this unique approach that may facilitate identifications of novel targets for next generation antibody therapies and development of real time preclinical tumor models.


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