Public Web-based databases are essential for present-day biological research: they i) store the results of past laboratory experiments; ii) guide the focus of future ones; and, iii) allow all to benefit from the wealth of information they contain. Many new databases are born each year; but how long do they live? This study looked at the 18-year survival of 326 databases. Over 60% were dead within that time period, and a further 14% were archived, no longer updated. Those that survived were, for the most part, important to their institution's main focus, and had core institutional support. Database longevity depends on the existence of infrastructures that are underpinned by long-term financial strategies. Researchers and funders need to consider the ramifications for the security of their data, and of the financial investments in them, if they choose to create new databases independently of core infrastructures.
Deficiency of the tumor suppressor Merlin causes development of schwannoma, meningioma, and ependymoma tumors, which can occur spontaneously or in the hereditary disease neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Surgery and radiotherapy are current first-line treatments; however, tumors frequently recur with limited treatment options. Here, we use human Merlin-negative schwannoma and meningioma primary cells to investigate the involvement of the endogenous retrovirus HERV-K in tumor development. HERV-K proteins previously implicated in tumorigenesis were overexpressed in schwannoma and all meningioma grades, and disease-associated CRL4DCAF1 and YAP/TEAD pathways were implicated in this overexpression. In normal Schwann cells, ectopic overexpression of HERV-K Env increased proliferation and upregulated expression of c-Jun and pERK1/2, which are key components of known tumorigenic pathways in schwannoma, JNK/c-Jun, and RAS/RAF/MEK/ERK. Furthermore, FDA-approved retroviral protease inhibitors ritonavir, atazanavir, and lopinavir reduced proliferation of schwannoma and grade I meningioma cells. These results identify HERV-K as a critical regulator of progression in Merlin-deficient tumors and offer potential strategies for therapeutic intervention. Significance: The endogenous retrovirus HERV-K activates oncogenic signaling pathways and promotes proliferation of Merlin-deficient schwannomas and meningiomas, which can be targeted with antiretroviral drugs and TEAD inhibitors.
Background: The cell-surface attachment protein (Env) of the HERV-K(HML-2) lineage of endogenous retroviruses is a potentially attractive tumour-associated antigen for anti-cancer immunotherapy. The human genome contains around 100 integrated copies (called proviruses or loci) of the HERV-K(HML-2) virus and we argue that it is important for therapy development to know which and how many of these contribute to protein expression, and how this varies across tissues. We measured relative provirus expression in HERV-K(HML-2), using enriched RNA-Seq analysis with both short-and long-read sequencing, in three Mantle Cell Lymphoma cell lines (JVM2, Granta519 and REC1). We also confirmed expression of the Env protein in two of our cell lines using Western blotting, and analysed provirus expression data from all other relevant published studies. Results: Firstly, in both our and other reanalysed studies, approximately 10% of the transcripts mapping to HERV-K(HML-2) came from Env-encoding proviruses. Secondly, in one cell line the majority of the protein expression appears to come from one provirus (12q14.1). Thirdly, we find a strong tissue-specific pattern of provirus expression. Conclusions: A possible dependency of Env expression on a single provirus, combined with the earlier observation that this provirus is not present in all individuals and a general pattern of tissue-specific expression among proviruses, has serious implications for future HERV-K(HML-2)-targeted immunotherapy. Further research into HERV-K(HML-2) as a possible tumour-associated antigen in blood cancers requires a more targeted, proteome-based, screening protocol that will consider these polymorphisms within HERV-K(HML-2). We include a plan (and necessary alignments) for such work.
Our results suggest that the function of CD10 may change during tumour evolution. It may inhibit cell motility in early-stage disease whilst promoting cell viability in late-stage disease. It has a complex role and further studies are needed to elucidate the suitability of CD10 as a prognostic marker or therapeutic target.
Deficiency of the tumor suppressor Merlin causes the development of schwannoma, meningioma and ependymoma tumors. These can occur spontaneously or in the hereditary disease Neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Currently available treatments are surgery or radiosurgery which are only partially effective, with tumors frequently reoccurring and in case of meningioma often as a higher grade. There is an urgent need for effective drug treatments.In this study, we investigated the role of Human Endogenous Retrovirus Type K (HERV-K) and its targetability in Merlin negative schwannoma and meningioma tumors by using tissues and primary cells isolated form patients employing immunohistochemistry, immunocytochemistry, western blotting and proliferation assays. We demonstrate that HERV-K proteins are overexpressed in Merlin negative schwannoma and all meningioma grades. Furthermore, we implicate CRL4DCAF1 and YAPT/EAD Hippo pathway in this overexpression and suggest that exosome transport of the HERV-K Envelope (Env) protein might contribute to schwannoma development. We also show that: (i) Ectopic overexpression of HERV-K Env in normal Schwann cells increased proliferation and upregulated the transcription factor c-Jun. Env overexpression also increased activity of the extracellular signal-regulated kinase 1/2 (pERK1/2), a known mitogenic pathway in schwannoma. (ii) An anti-Env monoclonal antibody decreased pERK1/2 and reduced proliferation of schwannoma cells. iii) FDA-approved retroviral protease inhibitors Ritonavir, Atazanavir and Lopinavir decreased pERK1/2 and cyclin D1 and reduced proliferation of schwannoma and grade I meningioma cells. We provide evidence for HERV-K Env contributing to the development of NF2-associated schwannomas and meningiomas. Considering the urgent need of drugs to treat NF2, we suggest the trialling of antiretroviral protease inhibitors, and consideration of anti-HERV-K Env immunotherapy, as well as TEAD-specific inhibitors in these patients. The above treatments would also be potentially beneficial for patients with other tumors caused by Merlin deficiency. Citation Format: Sylwia Ammoun, Emmanuel A. Maze, Bora Agit, Robert Belshaw, C Oliver Hanemann. Human endogenous retrovirus type K promotes proliferation of Merlin negative schwannoma and meningioma which can be inhibited by anti-retroviral and anti-TEAD drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1164.
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