RESUMEN
Plasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can be specifically targeted by recombinant VAR2CSA (rVAR2). In tumors, placental-like CS chains are linked to a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4. The rVAR2 protein localizes to tumors in vivo and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin compounds strongly inhibits in vivo tumor cell growth and metastasis. Our data demonstrate how an evolutionarily refined parasite-derived protein can be exploited to target a common, but complex, malignancy-associated glycosaminoglycan modification.
Asunto(s)
Antígenos de Protozoos/genética , Sulfatos de Condroitina/metabolismo , Melanoma Experimental/terapia , Placenta/metabolismo , Proteínas Recombinantes/administración & dosificación , Neoplasias Cutáneas/terapia , Animales , Antígenos de Protozoos/metabolismo , Línea Celular Tumoral , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Femenino , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Receptores de Hialuranos/metabolismo , Melanoma Experimental/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Terapia Molecular Dirigida , Oligopéptidos/genética , Oligopéptidos/metabolismo , Especificidad de Órganos , Embarazo , Proteínas Recombinantes/farmacología , Neoplasias Cutáneas/metabolismoRESUMEN
High-throughput transcriptome sequencing allows identification of cancer-related changes that occur at the stages of transcription, pre-messenger RNA (mRNA), and splicing. In the current study, we devised a pipeline to predict novel alternative splicing (AS) variants from high-throughput transcriptome sequencing data and applied it to large sets of tumor transcriptomes from The Cancer Genome Atlas (TCGA). We identified two novel tumor-associated splice variants of matriptase, a known cancer-associated gene, in the transcriptome data from epithelial-derived tumors but not normal tissue. Most notably, these variants were found in 69% of lung squamous cell carcinoma (LUSC) samples studied. We confirmed the expression of matriptase AS transcripts using quantitative reverse transcription PCR (qRT-PCR) in an orthogonal panel of tumor tissues and cell lines. Furthermore, flow cytometric analysis confirmed surface expression of matriptase splice variants in chinese hamster ovary (CHO) cells transiently transfected with cDNA encoding the novel transcripts. Our findings further implicate matriptase in contributing to oncogenic processes and suggest potential novel therapeutic uses for matriptase splice variants.