title: Quantitative proteomic profiling of pleomorphic human sarcoma identifies CLIC1 as a dominant pro-oncogenic receptor expressed in diverse sarcoma types.
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.
authors.affiliation: University of Edinburgh , Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research Centre, South Crewe Road, Edinburgh EH4 2XR, United Kingdom.
authors.forename: Euan
authors.initials: E
authors.lastname: Murray
authors.forename: Lenka
authors.initials: L
authors.lastname: Hernychová
authors.forename: Michaela
authors.initials: M
authors.lastname: Scigelova
authors.forename: Jenny
authors.initials: J
authors.lastname: Ho
authors.forename: Marta
authors.initials: M
authors.lastname: Nekulova
authors.forename: John Robert
authors.initials: JR
authors.lastname: O'Neill
authors.forename: Rudolf
authors.initials: R
authors.lastname: Nenutil
authors.forename: Karel
authors.initials: K
authors.lastname: Vesely
authors.forename: Sinclair R
authors.initials: SR
authors.lastname: Dundas
authors.forename: Catharine
authors.initials: C
authors.lastname: Dhaliwal
authors.forename: Hannah
authors.initials: H
authors.lastname: Henderson
authors.forename: Richard L
authors.initials: RL
authors.lastname: Hayward
authors.forename: Donald M
authors.initials: DM
authors.lastname: Salter
authors.forename: Bořivoj
authors.initials: B
authors.lastname: Vojtěšek
authors.forename: Ted R
authors.initials: TR
authors.lastname: Hupp
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D007890:Leiomyosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D060149:Tetraspanin 30 / Q000235:genetics / Q000378:metabolism
chemical_list: C501966:CLIC1 protein, human; C464459:CLIC4 protein, human; D018118:Chloride Channels; D018960:Hyaluronan Receptors; D020543:Proteome; D060149:Tetraspanin 30