Satellite repeat RNA expression in epithelial ovarian cancer associates with a tumor-immunosuppressive phenotype
Rebecca L. Porter, … , Benjamin D. Greenbaum, David T. Ting
Rebecca L. Porter, … , Benjamin D. Greenbaum, David T. Ting
Published June 16, 2022
Citation Information: J Clin Invest. 2022;132(16):e155931. https://doi.org/10.1172/JCI155931.
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Research Article Oncology

Satellite repeat RNA expression in epithelial ovarian cancer associates with a tumor-immunosuppressive phenotype

Abstract

Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that human satellite II (HSATII) satellite repeat expression was highly associated with epithelial-mesenchymal transition (EMT) and anticorrelated with IFN-response genes indicative of a more aggressive phenotype. SATII expression — and its correlation with EMT and anticorrelation with IFN-response genes — was also found in ovarian cancer RNA-Seq data and was associated with significantly shorter survival in a second independent cohort of patients with ovarian cancer. Repeat RNAs were enriched in tumor-derived extracellular vesicles capable of stimulating monocyte-derived macrophages, demonstrating a mechanism that alters the tumor microenvironment with these viral-like sequences. Targeting of HSATII with antisense locked nucleic acids stimulated IFN response and induced MHC I expression in ovarian cancer cell lines, highlighting a potential strategy of modulating the repeatome to reestablish antitumor cell immune surveillance.

Authors

Rebecca L. Porter, Siyu Sun, Micayla N. Flores, Emily Berzolla, Eunae You, Ildiko E. Phillips, Neelima KC, Niyati Desai, Eric C. Tai, Annamaria Szabolcs, Evan R. Lang, Amaya Pankaj, Michael J. Raabe, Vishal Thapar, Katherine H. Xu, Linda T. Nieman, Daniel C. Rabe, David L. Kolin, Elizabeth H. Stover, David Pepin, Shannon L. Stott, Vikram Deshpande, Joyce F. Liu, Alexander Solovyov, Ursula A. Matulonis, Benjamin D. Greenbaum, David T. Ting

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Figure 1

Diverse repeat RNA expression profiles are present in epithelial cancers and cluster tumors by tissue of origin distinctly compared with coding gene-based clustering.

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Diverse repeat RNA expression profiles are present in epithelial cancers...
(A) Graphical abstract of experimental strategy. (B) Proportion of the total transcriptome represented by mRNA, ribosomal RNA/transfer RNA (rRNA/tRNA), annotated repeats, and nonannotated repeats, averaged across all epithelial ovarian cancer (EOC) cell lines. (C) Quantification of subclasses of repeat RNAs across EOC models using total RNA-Seq expressed as proportion of total transcription, including coding and noncoding reads in each cell line or in patient-derived cells. (D) Heatmap and hierarchical clustering of EOC (green), pancreatic ductal adenocarcinoma (PDAC; purple), and colorectal cancer (CRC; gold) cell lines by coding gene expression, including all coding genes that were differentially expressed between any 2 cell lines (adjusted P < 0.05 and |log2fold change| >1). Expression is plotted as scaled log2(normalized counts per million). Pie charts C1–C5 depict the cancer-type composition of each cluster as labeled. (E) Heatmap and hierarchical clustering of EOC (green), PDAC (purple), and CRC (gold) cell lines by repeat RNA expression, including all repeat species that were differentially expressed between any 2 cell lines (adjusted P < 0.05 and |log2fold change| >1). Expression is plotted as scaled log2(normalized counts per million). Major clusters defined by similar repeat expression profiles are outlined by black boxes. Pie charts R1–R5 depict the cancer-type composition of each cluster as labeled.