Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma

Shah, Ashish H.; Rivas, Sarah R.; Doucet-O’Hare, Tara T.; Govindarajan, Vaidya; DeMarino, Catherine; Wang, Tongguang; Ampie, Leonel; Zhang, Yong; Banasavadi-Siddegowda, Yeshavanth Kumar; Walbridge, Stuart; Maric, Dragan; Garcia-Montojo, Marta; Suter, Robert K.; Lee, Myoung-Hwa; Zaghloul, Kareem A.; Steiner, Joseph; Elkahloun, Abdel G.; Chandar, Jay; Seetharam, Deepa; Desgraves, Jelisah; Li, Wenxue; Johnson, Kory; Ivan, Michael E.; Komotar, Ricardo J.; Gilbert, Mark R.; Heiss, John D.; Nath, Avindra

doi:10.1172/jci167929

Cited by 20 publications

(24 citation statements)

References 70 publications

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“…We and other researchers have shown that HERV-K envelope glycoproteins harbor immunosuppressive activity and are enriched in tumor tissues of a variety of cancers and as sociated with poor outcome [11][12][13][14][15][16]. In the present study, we, for the first time, demonstrated that subtype-specific K102-Env, but not K108-Env, is a novel serum biomarker for evaluatin g immunosuppressive status and disease stage of patients with cancer.…”

Section: Discussionsupporting

confidence: 56%

“…Previous studies have revealed that HERV-K-Env proteins are enriched in tumor tissues of a variety of cancers [11][12][13][14][15][16], and there are a number of HERV-K family members, but it is unknown whether K-Env proteins are present in circulating blood of patients with cancer. Of the HERV-K family, only HERV-K108 and HERV-K102 proviruses contain intact ORFs [10], thus, we focused on K108-Env and K102-Env in this study.…”

Section: K108-env Proteins Are Present In Serum Of Both Patients With...mentioning

confidence: 99%

“…Although high levels of HERV-K-Env in tumor tissues imply poor outcome [11][12][13][14][15][16], it is unknown whether increased circulating K102-Env in blood is associated with disease activity. We next analyzed correlation of circulating K102-Env level and cancer stage in PDAC and HCC, and we found increased circulating K102-Env proteins mainly in the sera from patients with advanced or metastatic cancer.…”

Section: Serum K102 Env Levels Are Associated With Advanced Cancersmentioning

confidence: 99%

“…Several HERV-K family members, such as HERV-K102 and HERV-K108, are unique to humans and continue to evolve [9,10]. We, and other researchers, have previously demonstrated that HERV-K envelope glycoproteins (K-Env), which consist of a surface unit (SU) and a transmembrane (TM) subunit with potential immunosuppressive activity, are enriched in tumor tissues and correlate with poor outcome in cancers that include acute myeloid leukemia (AML), pancreatic duct adenocarcinoma (PDAC), lung cancer, and glioma [11][12][13][14][15][16]. Previous studies have shown that reactivation of HERV-K is associated with immunosuppressive status in some diseases.…”

Section: Introductionmentioning

confidence: 99%

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Subtype-specific HERV-K102 envelope is a novel serum immunosuppressive biomarker and therapeutic target of cancer

Xu,

Gong,

et al. 2024

Preprint

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Background: Immune dysfunction is a hallmark of cancer and plays critical roles in immunotherapy resistance, but there is no serum biomarker that can be used to evaluate immune-dysfunction status of cancer patients. Here, we identified subtype-specific HERV-K102 envelope (K102-Env) with immunosuppressive activity in circulating blood as a novel serum immunosuppressive biomarker of cancer. Methods: We first generated monoclonal antibodies against K102-Env with high sensitivity and specificity, and we developed an ELISA assay for serum K102-Env. We then investigated whether K102-Env and K108-Env proteins are present in circulating blood of cancer patients. Results: We detected K108-Env in 63.33% of patients with pancreatic duct adenocarcinoma (PDAC) (n = 30) and 63% of healthy sera (n = 30). In contrast, K102-Env markedly increased in patients with PDAC, hepatocellular carcinoma (HCC), and non-small cell lung cancer (NSCLC) compared with healthy controls (p < 0.01). The positive rates of K102-Env were 34.00%, 39%, and 28.0% in PDAC, HCC, and NSCLC, respectively, whereas only 5.0% of healthy individuals had marginally increased K102-Env. In patients with PDAC, K102-Env was 36.63-fold higher than in sera of healthy controls. K102-Env significantly upregulated PD-1/PD-L1 and c-Myc expression levels of T cells. Importantly, serum K102-Env levels correlated well with advanced cancers and tumor biomarkers CA19-9 and AFP. Conclusion: These findings indicate that circulating K102-Env is a novel serum biomarker for evaluating immunosuppressive status and disease stage of patients with cancer, and it also provides a potential target for cancer immunotherapy.

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Section: Discussionsupporting

confidence: 56%

Section: K108-env Proteins Are Present In Serum Of Both Patients With...mentioning

confidence: 99%

Section: Serum K102 Env Levels Are Associated With Advanced Cancersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Subtype-specific HERV-K102 envelope is a novel serum immunosuppressive biomarker and therapeutic target of cancer

Xu,

Gong,

et al. 2024

Preprint

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“…The combined use of MATES’s TE expression quantification and conventional gene expression analysis allowed us to pinpoint distinct cell populations within the glioblastoma microenvironment, as shown in the UMAP plots (Fig.3 ab). Significantly, we observed certain TEs with expression patterns linked to crucial glioma gene markers like EGFR [29, 30] and TE markers including HUERS-P1-int [31], HERVK-int [32], along with immune cell gene markers such as CD74 [33, 34] and TE marker LTR2B [35, 36] (Fig.3 b). This correlation suggests TEs may play a significant role in the development of glioblastoma, potentially affecting both tumor heterogeneity and immune response.…”

Section: Resultsmentioning

confidence: 99%

MATES: A Deep Learning-Based Model for Locus-specific Quantification of Transposable Elements in Single Cell

Wang,

Zheng,

Zhang

et al. 2024

Preprint

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Transposable elements (TEs) are crucial for genetic diversity and gene regulation. Current single-cell quantification methods often align multi-mapping reads to either `best-mapped' or `random-mapped' locations and categorize them at sub-family levels, overlooking the biological necessity for accurate, locus-specific TE quantification. Moreover, these existing methods are primarily designed for and focused on transcriptomics data, which restricts their adaptability to single-cell data of other modalities. To address these challenges, here we introduce MATES, a novel deep-learning approach that accurately allocates multi-mapping reads to specific loci of TEs, utilizing context from adjacent read alignments flanking the TE locus. When applied to diverse single-cell omics datasets, MATES shows improved performance over existing methods, enhancing the accuracy of TE quantification and aiding in the identification of marker TEs for identified cell populations. This development enables exploring single-cell heterogeneity and gene regulation through the lens of TEs, offering a transformative tool for the single-cell genomics community.

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The expression analysis of human endogenous retrovirus‐K Env, Np9, and Rec transcripts in cervical cancer

Soleimani‐Jelodar,

Arashkia,

Shoja

et al. 2024

Journal of Medical Virology

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While infection with high‐risk human papillomavirus (HPV) types is necessary for cervical cancer (CC) development, it is not enough, and other risk factors are required. Several studies have reported the activation of HERV‐K in different cancers; however, the investigation of HERV‐K expression levels in CC is scarce. In this study, it was hypothesized that activation of HERV‐K could play an essential role in CC development. In this order, the expression levels of HERV‐K Env, Np9, and Rec transcripts were investigated on 147 normal to CC uterine cervical tissues using quantitative real‐time PCR. The significantly higher levels of HERV‐K Env and Np9 transcripts were found in patients with cervical intraepithelial neoplasia (CIN) II−III and CC groups compared to those in the normal/CIN I group. Expression of Rec transcript was also higher only in the CC group than normal/CIN I group. Among CC patients, meaningfully higher levels of HERV‐K Env and Np9 transcripts were found in patients with squamous cell carcinoma rather than in adenocarcinoma. When only the HPV 16 positive samples were investigated, it was found that the mean difference in Env and Np9 mRNA levels was meaningfully higher among precancer lesions and the cancer group in comparison with the normal group. However, the Rec mRNA level showed no significant differences. The association between the expression of HERV‐K genes was investigated, and a significant positive correlation of Env expression with Np9 transcript was found only in the group with precancer lesions (R = 0.6, p = 0.0037). Moreover, a significant positive correlation was found between Rec and Np9 transcripts in patients with normal cervix tissues (R = 0.26, p = 0.033). However, no correlations were observed between the expression of Env and Rec in the three groups. In conclusion, our results showed that HERV‐K transcripts, especially Env and Np9, upregulated during cervical lesion progression. These findings highlight the potential use of HERV‐K Env and Np9 as biomarkers for CC diagnosis and prognosis. Further investigation is needed to determine the clinical utility of these markers and whether targeting HERV‐K oncogenes could be a viable therapeutic strategy for CC.

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Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma

Cited by 20 publications

References 70 publications

Subtype-specific HERV-K102 envelope is a novel serum immunosuppressive biomarker and therapeutic target of cancer

Subtype-specific HERV-K102 envelope is a novel serum immunosuppressive biomarker and therapeutic target of cancer

MATES: A Deep Learning-Based Model for Locus-specific Quantification of Transposable Elements in Single Cell

The expression analysis of human endogenous retrovirus‐K Env, Np9, and Rec transcripts in cervical cancer

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