Dataset Information

Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune Evasion.

ABSTRACT: BACKGROUND:Ewing sarcoma (EWS) manifests one of the lowest somatic mutation rates of any cancer, leading to a scarcity of druggable mutations and neoantigens. Immunotherapeutics targeting differentially expressed cell surface antigens could provide therapeutic benefit for such tumors. Pregnancy-associated plasma protein A (PAPP-A) is a cell membrane-associated proteinase produced by the placenta that promotes fetal growth by inducing insulinlike growth factor (IGF) signaling. METHODS:By comparing RNA expression of cell surface proteins in EWS (n?=?120) versus normal tissues (n?=?42), we comprehensively characterized the surfaceome of EWS to identify highly differentially expressed molecules. Using CRISPR/Cas-9 and anti-PAPP-A antibodies, we investigated biological roles for PAPP-A in EWS in vitro and in vivo in NSG xenograft models and performed RNA-sequencing on PAPPA knockout clones (n?=?5) and controls (n?=?3). All statistical tests were two-sided. RESULTS:EWS surfaceome analysis identified 11 highly differentially overexpressed genes, with PAPPA ranking second in differential expression. In EWS cell lines, genetic knockout of PAPPA and treatment with anti-PAPP-A antibodies revealed an essential survival role by regulating local IGF-1 bioavailability. MAb-mediated PAPPA inhibition diminished EWS growth in orthotopic xenografts (leg area mm2 at day 49 IgG2a control (CTRL) [n?=?14], mean?=?397.0, SD?=?86.1 vs anti-PAPP-A [n?=?14], mean?=?311.7, SD?=?155.0; P =?.03; median OS anti-PAPP-A?=?52.5?days, 95% CI?=?46.0 to 63.0?days vs IgG2a?=?45.0?days, 95% CI?=?42.0 to 52.0?days; P?=?.02) and improved the efficacy of anti-IGF-1R treatment (leg area mm2 at day 49 anti-PAPP-A + anti-IGF-1R [n?=?15], mean?=?217.9, SD?=?148.5 vs IgG2a-CTRL; P?

SUBMITTER: Heitzeneder S

PROVIDER: S-EPMC6748813 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune Evasion.

Heitzeneder Sabine S Sotillo Elena E Shern Jack F JF Sindiri Sivasish S Xu Peng P Jones Robert R Pollak Michael M Noer Pernille R PR Lorette Julie J Fazli Ladan L Alag Anya A Meltzer Paul P Lau Ching C Conover Cheryl A CA Oxvig Claus C Sorensen Poul H PH Maris John M JM Khan Javed J Mackall Crystal L CL

Journal of the National Cancer Institute 20190901 9

<h4>Background</h4>Ewing sarcoma (EWS) manifests one of the lowest somatic mutation rates of any cancer, leading to a scarcity of druggable mutations and neoantigens. Immunotherapeutics targeting differentially expressed cell surface antigens could provide therapeutic benefit for such tumors. Pregnancy-associated plasma protein A (PAPP-A) is a cell membrane-associated proteinase produced by the placenta that promotes fetal growth by inducing insulinlike growth factor (IGF) signaling.<h4>Methods< ...[more]

PMID: 30698726

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Project description:MicroRNAs (miRs) have been identified as potent regulators of both normal development and the hallmarks of cancer. Targeting of microRNAs has been shown to have preclinical promise, and select miR-based therapies are now in clinical trials. Ewing Sarcoma is a biologically aggressive pediatric cancer with little change in clinical outcomes despite improved chemotherapeutic regimens. There is a substantial need for new therapies to improve Ewing Sarcoma outcomes and to prevent chemotherapy-related secondary sequelae. Most Ewing Sarcoma tumors are driven by the EWS/Fli-1 fusion oncoprotein, acting as a gain-of-function transcription factor causing dysregulation of a variety of targets, including microRNAs. Our previous studies, and those of others, have identified upregulation of miRs belonging to the related miR-17~92a, miR-106b~25, and miR-106a~363 clusters in Ewing Sarcoma. However, the functional consequences of this have not been characterized, nor has miR blockade been explored as an anti-cancer strategy in Ewing Sarcoma. To simulate a potential therapeutic approach, we examined the effects of blockade of these clusters, and their component miRs. Using colony formation as a read-out, we find that blockade of selected individual cluster component miRs, using specific inhibitors, has little or no effect. Combinatorial inhibition using miR "sponge" methodology, on the other hand, is inhibitory to colony formation, with blockade of whole clusters generally more effective than blockade of miR families. We show that a miR-blocking sponge directed against the poorly characterized miR-106a~363 cluster is a particularly potent inhibitor of clonogenic growth in a subset of Ewing Sarcoma cell lines. We further identify upregulation of miR-15a as a downstream mechanism contributing to the miR-106a~363 sponge growth-inhibitory effect. Taken together, our studies provide support for a pro-oncogenic role of the miR-106a~363 cluster in Ewing Sarcoma, and identify miR-106a~363 blockade, as well as miR-15a replacement, as possible strategies for inhibition of Ewing Sarcoma growth.

Dataset Information

Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune Evasion.

Publications

Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune Evasion.

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