NDLI: Heterogeneity of Pancreatic Cancer Metastases in a Single Patient Revealed by Quantitative Proteomics*

Content Provider	PubMed Central
Author	Kim, Min-sik Zhong, Yi Shinichi, Yachida Rajeshkumar, N. V. Abel, Melissa L. Marimuthu, Arivusudar Mudgal, Keshav Hruban, Ralph H. Poling, Justin S. Tyner, Jeffrey W. Maitra, Anirban Iacobuzio-donahue, Christine A. Pandey, Akhilesh
Copyright Year	2014
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.
Related Links	http://dx.doi.org/10.1074/mcp.m114.038547
Ending Page	2811
Page Count	9
Starting Page	2803
File Format	PDF
ISSN	15359476
e-ISSN	15359484
Journal	Molecular & Cellular Proteomics : MCP
Issue Number	11
Volume Number	13
Language	English
Publisher	The American Society for Biochemistry and Molecular Biology
Publisher Date	2014-11-01
Access Restriction	Open
Rights Holder	The American Society for Biochemistry and Molecular Biology
Subject Keyword	Analytical Chemistry Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine Analytical Chemistry Molecular Biology Biochemistry

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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