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Multi-level Proteomics Identifies CT45 as a Chemosensitivity Mediator and Immunotherapy Target in Ovarian Cancer.

Cell | 2018

Most high-grade serous ovarian cancer (HGSOC) patients develop resistance to platinum-based chemotherapy and recur, but 15% remain disease free over a decade. To discover drivers of long-term survival, we quantitatively analyzed the proteomes of platinum-resistant and -sensitive HGSOC patients from minute amounts of formalin-fixed, paraffin-embedded tumors. This revealed cancer/testis antigen 45 (CT45) as an independent prognostic factor associated with a doubling of disease-free survival in advanced-stage HGSOC. Phospho- and interaction proteomics tied CT45 to DNA damage pathways through direct interaction with the PP4 phosphatase complex. In vitro, CT45 regulated PP4 activity, and its high expression led to increased DNA damage and platinum sensitivity. CT45-derived HLA class I peptides, identified by immunopeptidomics, activate patient-derived cytotoxic T cells and promote tumor cell killing. This study highlights the power of clinical cancer proteomics to identify targets for chemo- and immunotherapy and illuminate their biological roles.

Pubmed ID: 30241606 RIS Download

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: P30 CA014599
  • Agency: NCI NIH HHS, United States
    Id: R01 CA111882
  • Agency: NCI NIH HHS, United States
    Id: R01 CA169604

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This is a list of tools and resources that we have found mentioned in this publication.


Addgene (tool)

RRID:SCR_002037

Non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.

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ProteomeXchange (tool)

RRID:SCR_004055

A data repository for proteomic data sets. The ProteomeExchange consortium, as a whole, aims to provide a coordinated submission of MS proteomics data to the main existing proteomics repositories, as well as to encourage optimal data dissemination. ProteomeXchange provides access to a number of public databases, and users can access and submit data sets to the consortium's PRIDE database and PASSEL/PeptideAtlas.

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CTDatabase (tool)

RRID:SCR_007614

A database of information about each Cancer-Testis (CT) gene, its gene products and the immune response induced in cancer patients by these proteins. CT antigens are proteins normally expressed only in the human germ line but that are also present in a significant subset of malignant tumors. The practical importance of these proteins is that due to their restricted expression pattern they are frequently recognized by the immune system of cancer patients. Moreover, this antigenicity has raised the possibility of their being used as vaccines to actively stimulate immune responses in order to combat tumor growth. As a result worldwide research into many aspects of CT antigens is rapidly growing prompting the construction of this database as a resource for investigators involved in this area.

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Program to Reduce Incontinence by Diet and Exercise (tool)

RRID:SCR_009018

Randomized controlled trial being conducted at two clinical centers in the United States to learn more about the effects of weight loss on urinary incontinence. About 330 overweight women aged 30 or older will participate and will be followed for 18 months. Efficacy of weight reduction as a treatment for urinary incontinence will be examined at 6 months following the intensive weight control program, and the sustained impact of the intervention will be examined at 18 months. To increase the maintenance of weight reduction and facilitate evaluation of the enduring impact of weight loss on urinary incontinence, they propose to study a motivation-based weight maintenance program. At the end of the intensive weight control program, women randomized to the weight loss program will be randomized to either a 12-month skill-based maintenance intervention or to a motivation-based maintenance intervention. The maintenance interventions maximize the potential for sustained weight loss and will allow them to determine if long-term weight reduction will produce continued improvement in urinary incontinence.

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cBioPortal (tool)

RRID:SCR_014555

A portal that provides visualization, analysis and download of large-scale cancer genomics data sets.

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Phospho-Histone H2A.X (Ser139) Monoclonal Antibody (3F2) (antibody)

RRID:AB_559491

This monoclonal targets Phospho-Histone H2A.X (Ser139)

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FANCD2 antibody [EPR2302] (antibody)

RRID:AB_10862535

This monoclonal targets FANCD2 antibody [EPR2302]

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Anti-PPP4R3A polyclonal antibody (antibody)

RRID:AB_1079207

This polyclonal targets PPP4R3A

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Anti-PPP4R2 polyclonal antibody (antibody)

RRID:AB_10671231

This polyclonal targets PPP4R2

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Anti-β-Actin Antibody (antibody)

RRID:AB_476744

This monoclonal targets slightly modified β-cytoplasmic actin N-terminal peptide, Ac-Asp-Asp-Asp-Ile-Ala-Ala-Leu-Val-Ile-Asp-Asn-Gly-Ser-Gly-Lys, conjugated to KLH

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PPP4R3 Beta Antibody (antibody)

RRID:AB_597905

This unknown targets PPP4R3 Beta

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PPP4C Antibody (antibody)

RRID:AB_597901

This unknown targets PPP4C

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Anti-rabbit IgG, HRP-linked Antibody (antibody)

RRID:AB_2099233

This polyclonal secondary targets IgG

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Cleaved Caspase-3 (Asp175) Antibody (antibody)

RRID:AB_2341188

This polyclonal targets Cleaved Caspase-3 (Asp175)

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Phospho-Histone H2A.X (Ser139) (20E3) Rabbit mAb (antibody)

RRID:AB_2118009

This monoclonal targets Histone H2A.X, phospho (Ser139)

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GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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Stata (software resource)

RRID:SCR_012763

A Software resource for statistical analysis and presentation of graphics.

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MaxQuant (software resource)

RRID:SCR_014485

A quantitative proteomics software package for analyzing large-scale mass-spectrometric data sets. It is a set of algorithms that include peak detection and scoring of peptides, mass calibration, database searches for protein identification, protein quantification, and provides summary statistics.

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59M (cell line)

RRID:CVCL_2291

Cell line 59M is a Cancer cell line with a species of origin Homo sapiens (Human)

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MFM-223 (cell line)

RRID:CVCL_1408

Cell line MFM-223 is a Cancer cell line with a species of origin Homo sapiens (Human)

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HCC1143 (cell line)

RRID:CVCL_1245

Cell line HCC1143 is a Cancer cell line with a species of origin Homo sapiens (Human)

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