Quantitative Proteomic Profiling of Pleomorphic Human Sarcoma Identifies CLIC1 as a Dominant Pro-Oncogenic Receptor Expressed in Diverse Sarcoma Types

Euan Murray, Lenka Hernychova, Michaela Scigelova, Jenny Ho, Marta Nekulova, John Robert O'Neill, Rudolf Nenutil, Karel Vesely, Sinclair R. Dundas, Catharine Dhaliwal, Hannah Henderson, Richard L. Hayward, Donald M. Salter, Borivoj Vojtesek, Ted R. Hupp*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Sarcomas are rare forms of cancer with a high unmet clinical need that develop in connective tissue, such as muscle, bone, nerves, cartilage, and fat. The outcome for patients is poor, with surgery and postoperative radiotherapy the standard treatment for patients. A better understanding of the molecular pathology of sarcoma may allow for the development of novel therapeutics. There are dozens of sarcoma subtypes where there is a need for targetted therapeutics, with the most commonly studied including Ewing's sarcoma and osteosarcoma. Here we initiate a proteomics-based target-discovery program to define "dominant" pro-oncogenic signaling targets in the most common sarcoma in adults: high-grade pleiomorphic soft tissue sarcoma. We have carried out a proteome screen using tandem mass tag isobaric labeling on three high-grade undifferentiated pleomorphic sarcoma biopsies from different tissue sites. We identified the commonly dysregulated proteins within the three sarcomas and further validated the most penetrant receptor as CLIC1, using immunohistochemistry arising from two different population cohorts representing over 300 patients. The dominant expression of CLIC1 in a broad range of human sarcomas suggests that studying this relatively unexplored signaling pathway might provide new insights into disease mechanism and facilitate the development of new CLIC1 targeted therapeutics.

Original languageEnglish
Pages (from-to)2543-2559
Number of pages17
JournalJournal of Proteome Research
Volume13
Issue number5
Early online date24 Mar 2014
DOIs
Publication statusPublished - May 2014

Keywords

  • cancer
  • sarcoma
  • proteomics
  • receptor
  • pathology
  • CLIC1
  • CD44
  • CD63
  • chloride intracellular channell
  • squamous-cell carcinoma
  • soft-tissue sarcomas
  • immunoconjugate bivatuzumab mertansine
  • breast-cancer
  • phase-I
  • CD44V6-targeting immunoconjugate
  • therapeutic targets
  • gastric-cancer
  • ovarian-cancer

Cite this

Quantitative Proteomic Profiling of Pleomorphic Human Sarcoma Identifies CLIC1 as a Dominant Pro-Oncogenic Receptor Expressed in Diverse Sarcoma Types. / Murray, Euan; Hernychova, Lenka; Scigelova, Michaela; Ho, Jenny; Nekulova, Marta; O'Neill, John Robert; Nenutil, Rudolf; Vesely, Karel; Dundas, Sinclair R.; Dhaliwal, Catharine; Henderson, Hannah; Hayward, Richard L.; Salter, Donald M.; Vojtesek, Borivoj; Hupp, Ted R.

In: Journal of Proteome Research, Vol. 13, No. 5, 05.2014, p. 2543-2559.

Research output: Contribution to journalArticle

Murray, E, Hernychova, L, Scigelova, M, Ho, J, Nekulova, M, O'Neill, JR, Nenutil, R, Vesely, K, Dundas, SR, Dhaliwal, C, Henderson, H, Hayward, RL, Salter, DM, Vojtesek, B & Hupp, TR 2014, 'Quantitative Proteomic Profiling of Pleomorphic Human Sarcoma Identifies CLIC1 as a Dominant Pro-Oncogenic Receptor Expressed in Diverse Sarcoma Types', Journal of Proteome Research, vol. 13, no. 5, pp. 2543-2559. https://doi.org/10.1021/pr4010713
Murray, Euan ; Hernychova, Lenka ; Scigelova, Michaela ; Ho, Jenny ; Nekulova, Marta ; O'Neill, John Robert ; Nenutil, Rudolf ; Vesely, Karel ; Dundas, Sinclair R. ; Dhaliwal, Catharine ; Henderson, Hannah ; Hayward, Richard L. ; Salter, Donald M. ; Vojtesek, Borivoj ; Hupp, Ted R. / Quantitative Proteomic Profiling of Pleomorphic Human Sarcoma Identifies CLIC1 as a Dominant Pro-Oncogenic Receptor Expressed in Diverse Sarcoma Types. In: Journal of Proteome Research. 2014 ; Vol. 13, No. 5. pp. 2543-2559.
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AU - Ho, Jenny

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AU - O'Neill, John Robert

AU - Nenutil, Rudolf

AU - Vesely, Karel

AU - Dundas, Sinclair R.

AU - Dhaliwal, Catharine

AU - Henderson, Hannah

AU - Hayward, Richard L.

AU - Salter, Donald M.

AU - Vojtesek, Borivoj

AU - Hupp, Ted R.

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N2 - Sarcomas are rare forms of cancer with a high unmet clinical need that develop in connective tissue, such as muscle, bone, nerves, cartilage, and fat. The outcome for patients is poor, with surgery and postoperative radiotherapy the standard treatment for patients. A better understanding of the molecular pathology of sarcoma may allow for the development of novel therapeutics. There are dozens of sarcoma subtypes where there is a need for targetted therapeutics, with the most commonly studied including Ewing's sarcoma and osteosarcoma. Here we initiate a proteomics-based target-discovery program to define "dominant" pro-oncogenic signaling targets in the most common sarcoma in adults: high-grade pleiomorphic soft tissue sarcoma. We have carried out a proteome screen using tandem mass tag isobaric labeling on three high-grade undifferentiated pleomorphic sarcoma biopsies from different tissue sites. We identified the commonly dysregulated proteins within the three sarcomas and further validated the most penetrant receptor as CLIC1, using immunohistochemistry arising from two different population cohorts representing over 300 patients. The dominant expression of CLIC1 in a broad range of human sarcomas suggests that studying this relatively unexplored signaling pathway might provide new insights into disease mechanism and facilitate the development of new CLIC1 targeted therapeutics.

AB - Sarcomas are rare forms of cancer with a high unmet clinical need that develop in connective tissue, such as muscle, bone, nerves, cartilage, and fat. The outcome for patients is poor, with surgery and postoperative radiotherapy the standard treatment for patients. A better understanding of the molecular pathology of sarcoma may allow for the development of novel therapeutics. There are dozens of sarcoma subtypes where there is a need for targetted therapeutics, with the most commonly studied including Ewing's sarcoma and osteosarcoma. Here we initiate a proteomics-based target-discovery program to define "dominant" pro-oncogenic signaling targets in the most common sarcoma in adults: high-grade pleiomorphic soft tissue sarcoma. We have carried out a proteome screen using tandem mass tag isobaric labeling on three high-grade undifferentiated pleomorphic sarcoma biopsies from different tissue sites. We identified the commonly dysregulated proteins within the three sarcomas and further validated the most penetrant receptor as CLIC1, using immunohistochemistry arising from two different population cohorts representing over 300 patients. The dominant expression of CLIC1 in a broad range of human sarcomas suggests that studying this relatively unexplored signaling pathway might provide new insights into disease mechanism and facilitate the development of new CLIC1 targeted therapeutics.

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KW - immunoconjugate bivatuzumab mertansine

KW - breast-cancer

KW - phase-I

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