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Mol Cell Proteomics. 2014 Nov;13(11):2803-11. doi: 10.1074/mcp.M114.038547. Epub 2014 Jun 3.

Heterogeneity of pancreatic cancer metastases in a single patient revealed by quantitative proteomics.

Author information

1
From the ‡McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; §Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205;
2
‖Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231;
3
**Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231;
4
§§Departments of Cell, Developmental and Cancer Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Mailcode L592, Portland, Oregon 97239;
5
¶¶Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India;
6
‖‖School of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
7
‖Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231; **Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231;
8
From the ‡McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; ‖Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231; **Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231;
9
‖Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231; **Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231; pandey@jhmi.edu iacobuzc@mskcc.org.
10
From the ‡McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; §Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; ‖Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231; pandey@jhmi.edu iacobuzc@mskcc.org.

Abstract

Many patients with pancreatic cancer have metastases to distant organs at the time of initial presentation. Recent studies examining the evolution of pancreatic cancer at the genetic level have shown that clonal complexity of metastatic pancreatic cancer is already initiated within primary tumors, and organ-specific metastases are derived from different subclones. However, we do not yet understand to what extent the evolution of pancreatic cancer contributes to proteomic and signaling alterations. We hypothesized that genetic heterogeneity of metastatic pancreatic cancer results in heterogeneity at the proteome level. To address this, we employed a model system in which cells isolated from three sites of metastasis (liver, lung, and peritoneum) from a single patient were compared. We used a SILAC-based accurate quantitative proteomic strategy combined with high-resolution mass spectrometry to analyze the total proteome and tyrosine phosphoproteome of each of the distal metastases. Our data revealed distinct patterns of both overall proteome expression and tyrosine kinase activities across the three different metastatic lesions. This heterogeneity was significant because it led to differential sensitivity of the neoplastic cells to small molecule inhibitors targeting various kinases and other pathways. For example, R428, a tyrosine kinase inhibitor that targets Axl receptor tyrosine kinase, was able to inhibit cells derived from lung and liver metastases much more effectively than cells from the peritoneal metastasis. Finally, we confirmed that administration of R428 in mice bearing xenografts of cells derived from the three different metastatic sites significantly diminished tumors formed from liver- and lung-metastasis-derived cell lines as compared with tumors derived from the peritoneal metastasis cell line. Overall, our data provide proof-of-principle support that personalized therapy of multiple organ metastases in a single patient should involve the administration of a combination of agents, with each agent targeted to the features of different subclones.

PMID:
24895378
PMCID:
PMC4223473
DOI:
10.1074/mcp.M114.038547
[Indexed for MEDLINE]
Free PMC Article

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