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H-STS, L-STS and KRJ-I are not authentic GEPNET cell lines

Nature Genetics volume 51, pages 1426–1427 (2019)Cite this article

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To the Editor — We read with great interest the recent paper1 by Alvarez et al. In it, they use the VIPER algorithm2 to mine transcriptome data from 212 rare gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) for master-regulator proteins. Master-regulator proteins were confirmed by short-hairpin-RNA inhibition in the H-STS cell line, which was originally established from a hepatic metastasis of a small-intestinal GEPNET3. To determine whether a pharmacological intervention could revert the activity of identified master-regulator proteins, the authors analyzed the effects of 107 compounds on the transcriptomic profile of H-STS cells. Three selected hit compounds were then studied in an H-STS xenograft. Two of the three compounds, the histone deacetylase inhibitors entinostat and belinostat, were shown to inhibit tumor growth. On the basis of the results presented in the study by Alvarez et al., the US Food and Drug Administration has approved an Investigational New Drug Application for entinostat in GEPNETs (NCT03211988).

However, in a previously published study4, we concluded that H-STS is not an authentic model of the GEPNET disease. In fact, we have demonstrated that the previously presumed GEPNET cell lines H-STS, L-STS and KRJ-I are all misidentified lymphoblastoid cell lines (LCLs). LCLs are B cells immortalized by Epstein–Barr virus (EBV) infection5. LCLs can grow out of primary cultures prepared from solid tumors as soon as the immune-selection pressure is lost, such as in immunodeficient mice or in cell culture. We based our claims on observations that these cell lines strongly expressed the lymphoid and B-cell markers CD45 and CD20, that they were EBV positive and that they lacked characteristic GEPNET marker proteins, such as cytokeratins and endocrine markers. Furthermore, in contrast to other authentic GEPNET cell lines, they grew as sphere-forming cell suspensions.

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Data availability

RNA-seq data from H-STS replicates were downloaded from Gene Expression Omnibus, via accession code GSE96760. Raw RNA-seq data from Sahlgrenska University Hospital small-intestinal GEPNET tumors have been deposited in the European Genome-phenome Archive under accession code EGAS00001003358. Restrictions for download include submission of a data access application to a local data-access committee. The agreement met requires that the data be used for cancer research only and that variants cannot be cross-searched in other databases.

Code availability

Code used for transcriptomic classification is available at http://bitbucket.org/jowkar/gepnet_classification/.

References

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Acknowledgements

The results published here are based partly on previously processed data generated with the TCGA database (http://cancergenome.nih.gov/). E. Larsson (Lekholm) is acknowledged for previous funding and supervision of J. Karlsson. The groups are also funded by the Swedish Cancer Society, Vetenskapsrådet, Familjen Erling-Persson Foundation, Knut and Alice Wallenberg Foundation, Sjöberg Foundation, Assar Gabrielsson Foundation and Wilhelm and Martina Lundgren’s Foundations.

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Author notes

  1. These authors contributed equally: Tobias Hofving, Joakim Karlsson.

  2. These authors jointly supervised this work: Ola Nilsson, Jonas A. Nilsson.

Authors and Affiliations

  1. Department of Laboratory Medicine, Sahlgrenska Cancer Center, Institute of Biomedicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden

    Tobias Hofving & Ola Nilsson

  2. Sahlgrenska Translational Melanoma Group, Department of Surgery, Sahlgrenska Cancer Center, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden

    Joakim Karlsson

  3. Sahlgrenska Translational Melanoma Group, Departments of Surgery and Oncology, Sahlgrenska Cancer Center, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden

    Jonas A. Nilsson

Authors
  1. Tobias Hofving
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  2. Joakim Karlsson
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  3. Ola Nilsson
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  4. Jonas A. Nilsson
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Corresponding authors

Correspondence to Ola Nilsson or Jonas A. Nilsson.

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The authors declare no competing interests.

Supplementary information

Supplementary Information

Supplementary Note and Supplementary Figure 1

Reporting Summary

Supplementary Table 1

Six-nearest-neighbor classification of H-STS replicates, based on Spearman correlation. The cancer types of the top six correlating TCGA cancer samples and their respective frequency and average correlation.

Supplementary Table 2

Six-nearest-neighbor classification of small intestinal GEPNETs from Sahlgrenska University Hospital patients. The cancer types of the top six correlating TCGA samples and their respective frequencies are shown.

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Hofving, T., Karlsson, J., Nilsson, O. et al. H-STS, L-STS and KRJ-I are not authentic GEPNET cell lines. Nat Genet 51, 1426–1427 (2019). https://doi.org/10.1038/s41588-019-0490-z

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