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1.
Cells ; 11(15)2022 08 04.
Article in English | MEDLINE | ID: mdl-35954262

ABSTRACT

Synovial sarcoma is a rare translocation-driven cancer with poor survival outcomes, particularly in the advanced setting. Previous synovial sarcoma preclinical studies have relied on a small panel of cell lines which suffer from the limitation of genomic and phenotypic drift as a result of being grown in culture for decades. Patient-derived xenografts (PDX) are a valuable tool for preclinical research as they retain many histopathological features of their originating human tumour; however, this approach is expensive, slow, and resource intensive, which hinders their utility in large-scale functional genomic and drug screens. To address some of these limitations, in this study, we have established and characterised a novel synovial sarcoma cell line, ICR-SS-1, which is derived from a PDX model and is amenable to high-throughput drug screens. We show that ICR-SS-1 grows readily in culture, retains the pathognomonic SS18::SSX1 fusion gene, and recapitulates the molecular features of human synovial sarcoma tumours as shown by proteomic profiling. Comparative analysis of drug response profiles with two other established synovial sarcoma cell lines (SYO-1 and HS-SY-II) finds that ICR-SS-1 harbours intrinsic resistance to doxorubicin and is sensitive to targeted inhibition of several oncogenic pathways including the PI3K-mTOR pathway. Collectively, our studies show that the ICR-SS-1 cell line model may be a valuable preclinical tool for studying the biology of anthracycline-resistant synovial sarcoma and identifying new salvage therapies following failure of doxorubicin.


Subject(s)
Sarcoma, Synovial , Soft Tissue Neoplasms , Cell Line, Tumor , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Heterografts , Humans , Oncogene Proteins, Fusion/metabolism , Proteomics , Sarcoma, Synovial/genetics , Sarcoma, Synovial/metabolism , Sarcoma, Synovial/pathology
2.
Dis Model Mech ; 13(7)2020 07 14.
Article in English | MEDLINE | ID: mdl-32493768

ABSTRACT

SWATH-mass spectrometry (MS) enables accurate and reproducible proteomic profiling in multiple model organisms including the mouse. Here, we present a comprehensive mouse reference spectral library (MouseRefSWATH) that permits quantification of up to 10,597 proteins (62.2% of the mouse proteome) by SWATH-MS. We exploit MouseRefSWATH to develop an analytical pipeline for species-specific deconvolution of proteomic alterations in human tumour xenografts (XenoSWATH). This method overcomes the challenge of high sequence similarity between mouse and human proteins, facilitating the study of host microenvironment-tumour interactions from 'bulk tumour' measurements. We apply the XenoSWATH pipeline to characterize an intraductal xenograft model of breast ductal carcinoma in situ and uncover complex regulation consistent with stromal reprogramming, where the modulation of cell migration pathways is not restricted to tumour cells but also operates in the mouse stroma upon progression to invasive disease. MouseRefSWATH and XenoSWATH open new opportunities for in-depth and reproducible proteomic assessment to address wide-ranging biological questions involving this important model organism.


Subject(s)
Breast Neoplasms/metabolism , Carcinoma, Intraductal, Noninfiltrating/metabolism , Neoplasm Proteins/metabolism , Proteome , Proteomics , Stromal Cells/metabolism , Tandem Mass Spectrometry , Animals , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Cell Communication , Cell Line, Tumor , Chromatography, Liquid , Databases, Protein , Female , Heterografts , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Nude , Mice, SCID , NIH 3T3 Cells , Neoplasm Transplantation , Species Specificity , Stromal Cells/pathology , Tumor Microenvironment
3.
Expert Rev Anticancer Ther ; 19(11): 971-991, 2019 11.
Article in English | MEDLINE | ID: mdl-31665941

ABSTRACT

Introduction: Tyrosine kinases are key mediators of intracellular signaling cascades and aberrations in these proteins have been implicated in driving oncogenesis through the dysregulation of fundamental cellular processes including proliferation, migration, and apoptosis. As such, targeting these proteins with small molecule tyrosine kinase inhibitors (TKI) has led to significant advances in the treatment of a number of cancer types.Areas covered: Soft tissue sarcomas (STS) are a heterogeneous and challenging group of rare cancers to treat, but the approval of the TKI pazopanib for the treatment of advanced STS demonstrates that this class of drugs may have broad utility against a range of different sarcoma histological subtypes. Since the approval of pazopanib, a number of other TKIs have entered clinical trials to evaluate whether their activity in STS matches the promising results seen in other solid tumors. In this article, we review the emerging role of TKIs in the evolving landscape of sarcoma treatment.Expert opinion: As our biological understanding of response and resistance of STS to TKIs advances, we anticipate that patient management will move away from a 'one size fits all' paradigm toward personalized, multi-line, and patient-specific treatment regimens where patients are treated according to the underlying biology and genetics of their specific disease.


Subject(s)
Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Sarcoma/drug therapy , Sulfonamides/administration & dosage , Drug Resistance, Neoplasm , Humans , Indazoles , Precision Medicine , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Pyrimidines/pharmacology , Sarcoma/enzymology , Sarcoma/pathology , Sulfonamides/pharmacology
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