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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.
AuthorsMin-Sik Kim, Yi Zhong, Shinichi Yachida, N V Rajeshkumar, Melissa L Abel, Arivusudar Marimuthu, Keshav Mudgal, Ralph H Hruban, Justin S Poling, Jeffrey W Tyner, Anirban Maitra, Christine A Iacobuzio-Donahue, Akhilesh Pandey
JournalMolecular & cellular proteomics : MCP (Mol Cell Proteomics) Vol. 13 Issue 11 Pg. 2803-11 (Nov 2014) ISSN: 1535-9484 [Electronic] United States
PMID24895378 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Copyright© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Chemical References
  • Antineoplastic Agents
  • Benzocycloheptenes
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Triazoles
  • bemcentinib
  • Receptor Protein-Tyrosine Kinases
  • Axl Receptor Tyrosine Kinase
Topics
  • Animals
  • Antineoplastic Agents (therapeutic use)
  • Benzocycloheptenes (therapeutic use)
  • Cells, Cultured
  • Humans
  • Liver Neoplasms (drug therapy, genetics, secondary)
  • Lung Neoplasms (drug therapy, genetics, secondary)
  • Mass Spectrometry
  • Mice
  • Molecular Targeted Therapy
  • Pancreatic Neoplasms (drug therapy, genetics, pathology)
  • Peritoneal Neoplasms (drug therapy, genetics, secondary)
  • Precision Medicine
  • Protein Kinase Inhibitors (therapeutic use)
  • Proteomics
  • Proto-Oncogene Proteins (antagonists & inhibitors)
  • Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)
  • Signal Transduction (genetics)
  • Triazoles (therapeutic use)
  • Xenograft Model Antitumor Assays
  • Axl Receptor Tyrosine Kinase

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