title: Heterogeneity of pancreatic cancer metastases in a single patient revealed by quantitative proteomics.
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.
authors.affiliation: 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;
authors.forename: Min-Sik
authors.initials: MS
authors.lastname: Kim
authors.affiliation: ‖Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231;
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: ‖Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231;
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yachida
authors.affiliation: **Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231;
authors.forename: N V
authors.initials: NV
authors.lastname: Rajeshkumar
authors.affiliation: §§Departments of Cell, Developmental and Cancer Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Mailcode L592, Portland, Oregon 97239;
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Abel
authors.affiliation: ¶¶Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India;
authors.forename: Arivusudar
authors.initials: A
authors.lastname: Marimuthu
authors.affiliation: ‖‖School of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
authors.forename: Keshav
authors.initials: K
authors.lastname: Mudgal
authors.affiliation: ‖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;
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: ‖Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231;
authors.forename: Justin S
authors.initials: JS
authors.lastname: Poling
authors.affiliation: §§Departments of Cell, Developmental and Cancer Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Mailcode L592, Portland, Oregon 97239;
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: 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;
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: ‖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.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: 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.
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Pandey
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001567:Benzocycloheptenes / Q000627:therapeutic use*; D002478:Cells, Cultured; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D013058:Mass Spectrometry; D051379:Mice; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D040901:Proteomics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000235:genetics; D014230:Triazoles / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D001567:Benzocycloheptenes; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D014230:Triazoles; C548378:bemcentinib; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase