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

Min Sik Kim, Yi Zhong, Shinichi Yachida, N. V. Rajeshkumar, Melissa L. Abel, Arivusudar Marimuthu, Keshav Mudgal, Ralph H. Hruban, Justin S. Poling, Jeffrey Tyner, Anirban Maitra, Christine A. Iacobuzio-Donahue, Akhilesh Pandey

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2803-2811
Number of pages9
JournalMolecular and Cellular Proteomics
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2014

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Proteome
Pancreatic Neoplasms
Liver
Proteomics
Tumors
Neoplasm Metastasis
Protein-Tyrosine Kinases
Bearings (structural)
Cells
Heterografts
Mass spectrometry
Tyrosine
Phosphotransferases
Lung
Molecules
Cell Line
Neoplasms
Genetic Heterogeneity
Peritoneum
Mass Spectrometry

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Analytical Chemistry

Cite this

Kim, M. S., Zhong, Y., Yachida, S., Rajeshkumar, N. V., Abel, M. L., Marimuthu, A., ... Pandey, A. (2014). Heterogeneity of pancreatic cancer metastases in a single patient revealed by quantitative proteomics. Molecular and Cellular Proteomics, 13(11), 2803-2811. https://doi.org/10.1074/mcp.M114.038547

Heterogeneity of pancreatic cancer metastases in a single patient revealed by quantitative proteomics. / Kim, Min Sik; Zhong, Yi; Yachida, Shinichi; Rajeshkumar, N. V.; Abel, Melissa L.; Marimuthu, Arivusudar; Mudgal, Keshav; Hruban, Ralph H.; Poling, Justin S.; Tyner, Jeffrey; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Pandey, Akhilesh.

In: Molecular and Cellular Proteomics, Vol. 13, No. 11, 01.11.2014, p. 2803-2811.

Research output: Contribution to journalArticle

Kim, MS, Zhong, Y, Yachida, S, Rajeshkumar, NV, Abel, ML, Marimuthu, A, Mudgal, K, Hruban, RH, Poling, JS, Tyner, J, Maitra, A, Iacobuzio-Donahue, CA & Pandey, A 2014, 'Heterogeneity of pancreatic cancer metastases in a single patient revealed by quantitative proteomics', Molecular and Cellular Proteomics, vol. 13, no. 11, pp. 2803-2811. https://doi.org/10.1074/mcp.M114.038547
Kim, Min Sik ; Zhong, Yi ; Yachida, Shinichi ; Rajeshkumar, N. V. ; Abel, Melissa L. ; Marimuthu, Arivusudar ; Mudgal, Keshav ; Hruban, Ralph H. ; Poling, Justin S. ; Tyner, Jeffrey ; Maitra, Anirban ; Iacobuzio-Donahue, Christine A. ; Pandey, Akhilesh. / Heterogeneity of pancreatic cancer metastases in a single patient revealed by quantitative proteomics. In: Molecular and Cellular Proteomics. 2014 ; Vol. 13, No. 11. pp. 2803-2811.
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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.",
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