Systematic identification of cancer-specific MHC-binding peptides with RAVEN

Baldauf, Michaela C.; Gerke, Julia S.; Kirschner, A.; Blaeschke, Franziska; Effenberger, Manuel; Schober, Kilian; Rubío, Rebeca Alba; Kanaseki, Takayuki; Kıran, Merve Meryem; Dallmayer, Marlene; Musa, Julian; Akpolat, Nurset; Akatlı, Ayşe Nur; Rosman, Fernando Colonna; Özen, Özlem; Sugita, Shintaro; Hasegawa, Tadashi; Sugimura, Haruhiko; Baumhoer, Daniel; Knott, Maximilian M. L.; Sannino, Giuseppina; Marchetto, Aruna; Li, Jing; Busch, Dirk H.; Feuchtinger, Tobias; Ohmura, Shunya; Orth, Martin F.; Thiel, Uwe; Kirchner, Thomas; Grünewald, Thomas G.P.

doi:10.1101/193276

Cited by 6 publications

(14 citation statements)

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“…1a). These data were validated on the protein level in a tissue microarray 23,24 comprising the same normal tissue types and cancer entities (Fig. 1b,c).…”

Section: Sox6 Is Highly But Variably Expressed In Ewsmentioning

confidence: 82%

“…To explore the expression pattern of SOX6, we took advantage of a well-curated set of >750 DNA microarrays, which we established previously 23,24 , comprising 18 representative normal tissues types and 10 cancer entities. Comparative analyses revealed that SOX6 is overexpressed in EwS relative to normal tissues and other cancers (Fig.…”

Section: Sox6 Is Highly But Variably Expressed In Ewsmentioning

confidence: 99%

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Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma

Marchetto¹,

Ohmura²,

Orth³

et al. 2019

Preprint

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Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcriptionfactors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAAmicrosatellites (mSats) as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 -a physiological driver of proliferation of osteo-chondrogenic progenitors -by binding to an intronic GGAA-mSat, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments, we discovered that SOX6 interferes with the antioxidant system resulting in constitutively elevated reactive oxygen species (ROS) levels that create a therapeutic vulnerability toward the ROS-inducing drug Elesclomol. Collectively, our results exemplify how aberrant activation of a developmentaltranscription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.Ewing sarcoma (EwS) is the second most common bone or soft-tissue cancer in children and adolescents 1 . Even though the cell of origin of EwS is still debated, increasing evidence suggests that it may arise from mesenchymal stem cell (MSC)-derived early committed osteochondrogenic progenitors 2,3 . Indeed, EwS cells display a highly undifferentiated and embryonal phenotype. Clinically, EwS is a rapidly metastasizing cancer, and ~25% of cases are metastatic at initial diagnosis 1 . While great advances in treatment of localized disease have been achieved, established therapies still have limited success in advanced stages despite high toxicity 1 . Thus, more specific and in particular less toxic therapies are urgently required.As a genetic hallmark, EwS tumors express chimeric EWSR1-ETS (EwS breakpoint region 1 -E26 transformation specific) fusion oncoproteins generated through fusion of the EWSR1 gene and variable members of the ETS-family of transcription factors (TF), most commonly FLI1 (85% of all cases) 4,5 . Prior studies demonstrated that EWSR1-FLI1 acts as a pioneer transcription factor that massively rewires the tumor transcriptome ultimately promoting the malignant phenotype of EwS 6,7 . This is in part mediated through interference with and/or aberrant activation of developmental pathways 3,8 . Remarkably, EWSR1-FLI1 regulates approximately 40% of its target genes by binding to otherwise non-functional GGAA-

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“…1a). These data were validated on the protein level in a tissue microarray 23,24 comprising the same normal tissue types and cancer entities (Fig. 1b,c).…”

Section: Sox6 Is Highly But Variably Expressed In Ewsmentioning

confidence: 82%

Section: Sox6 Is Highly But Variably Expressed In Ewsmentioning

confidence: 99%

Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma

Marchetto¹,

Ohmura²,

Orth³

et al. 2019

Preprint

Self Cite

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“…The microarray datasets for cancer and normal tissues were downloaded from public repositories and processed as described previously 23 . Data were generated on Affymetrix HG-U133Plus2.0 microarrays and normalized simultaneously by Robust Multi-chip Average (RMA) using brainarray chip description files (CDF; ENTREZg, v21) yielding one optimized probe-set per gene 24,25 .…”

Section: Analysis Of Microarray Datamentioning

confidence: 99%

Targeting the CALCB/RAMP1-axis inhibits growth of Ewing sarcoma

Dallmayer¹,

Li²,

Ohmura³

et al. 2018

Preprint

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Ewing sarcoma (EwS) is an aggressive cancer caused by chromosomal translocations generating fusions of the EWSR1 gene with ETS transcription factors (in 85% FLI1). EWSR1-FLI1 induces gene expression via binding to enhancer-like GGAA-microsatellites, whose activity increases with the number of consecutive GGAA-repeats.Herein, we investigate the role of the secretory neuropeptide CALCB (calcitonin related polypeptide β) in EwS, which signals via the CGRP-(calcitonin gene-related peptide) receptor complex, containing RAMP1 (receptor activity modifying protein 1) as crucial part for receptor specificity. Analysis of 2,678 gene expression microarrays comprising 50 tumor entities and 71 normal tissue types revealed that CALCB is specifically and highly overexpressed in EwS. Timecourse knockdown experiments showed that CALCB expression is tightly linked to that of EWSR1-FLI1. Consistently, gene set enrichment analyses of genes whose expression in primary EwS is correlated to that of CALCB indicated that it is co-expressed with other EWSR1-FLI1 target genes and associated with signatures involved in stemness and proliferation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) data for EWSR1-FLI1 and histone marks from EwS cells demonstrated that EWSR1-FLI1 binds to a GGAA-microsatellite close to CALCB, which exhibits characteristics of an active enhancer. Reporter assays confirmed the strong EWSR1-FLI1-and length-dependent enhancer activity of this GGAA-microsatellite. Mass-spectrometry analyses of supernatants of EwS cell cultures demonstrated that CALCB is secreted by EwS cells.While short-term RNA interference-mediated CALCB knockdown had no effect on proliferation and clonogenic growth of EwS cells in vitro, its long-term knockdown decreased EwS growth in vitro and in vivo. Similarly, knockdown of RAMP1 reduced clonogenic/spheroidal growth and tumorigenicity, and small-molecule inhibitors directed against the CGRP-receptor comprising RAMP1 reduced growth of EwS.Collectively, our findings suggest that CALCB is a direct EWSR1-FLI1 target and that targeting the CALCB/RAMP1-axis may offer a new therapeutic strategy for inhibition of EwS growth.

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“…nicht exprimiert. Peptide aus Proteinen, die durch Transkription dieser KSGs entstehen, könnten immunogenes Potenzial haben und eine gezielte Immuntherapie ermöglichen (7).…”

Section: Kurzfassungen Der Vorträge Systematische Identifizierung Neuunclassified

“…Um ausgehend von öffentlich zugänglichen Genexpressionsdaten eine automatisierte und schnelle Identifizierung von KSG-codierten Peptiden mit hoher Affinität zu Major Histocompatibility Complexes (MHC) zu ermöglichen, entwickelten wir einen Algorithmus und implementierten diesen in eine benutzerfreundliche Software (RAVEN, Rich Analysis of Variable gene Expressions in Numerous tissues) (7).…”

Section: Kurzfassungen Der Vorträge Systematische Identifizierung Neuunclassified

Arbeitsgemeinschaft Knochentumoren e. V. (agkt)

Baldauf¹,

Gerke²,

Grünewald³

2018

Osteologie

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Systematic identification of cancer-specific MHC-binding peptides with RAVEN

Abstract: Immunotherapy can revolutionize anti-cancer therapy if specific targets are available.

Cited by 6 publications

References 50 publications

Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma

Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma

Targeting the CALCB/RAMP1-axis inhibits growth of Ewing sarcoma

Arbeitsgemeinschaft Knochentumoren e. V. (agkt)

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