bims-myxlip 2022-01-23 papers

Issue of 2022–01–23
two papers selected by
Laura Mannarino, Humanitas Research

Cells. 2022 Jan 08. pii: 207. [Epub ahead of print]11(2):

Establishment and Characterization of NCC-MFS5-C1: A Novel Patient-Derived Cell Line of Myxofibrosarcoma.

Ryuto Tsuchiya, Yuki Yoshimatsu, Rei Noguchi, Yooksil Sin, Takuya Ono, Taro Akiyama, Jun Sugaya, Eisuke Kobayashi, Naoki Kojima, Akihiko Yoshida, Seiji Ohtori, Akira Kawai, Tadashi Kondo.

Myxofibrosarcoma (MFS) is a highly aggressive malignancy with complex karyotypes and a postoperative recurrence tendency, owing to its strong invasiveness. Although systemic chemotherapy is considered in patients with unresectable MFS, the efficacy of conventional chemotherapy is hitherto unclear. Recently, drug screening analysis using a large number of tumor cell lines has been attempted to discover novel therapeutic candidate drugs for common cancers. However, the number of MFS cell lines is extremely small because of its low incidence-this hinders the conduction of screening studies and slows down the development of therapeutic drugs. To overcome this problem, we established a novel MFS cell line, NCC-MFS5-C1, which was shown to harbor typical MFS genetic abnormalities and thus had useful properties for in vitro studies. We conducted the largest integrated screening analysis of 210 drugs using NCC-MFS5-C1 cells along with four MFS cell lines, which we previously reported. Bortezomib (a proteasome inhibitor) and romidepsin (a histone deacetylase inhibitor) showed stronger antitumor effects than the standard drug, doxorubicin. Therefore, the NCC-MFS5-C1 cell line can potentially contribute to elucidating MFS pathogenesis and developing a novel MFS treatment.

Keywords: drug screening; histone deacetylase inhibitor; myxofibrosarcoma; patient-derived cell line; proteasome inhibitor; sarcoma

DOI: https://doi.org/10.3390/cells11020207

NAR Cancer. 2022 Mar;4(1): zcab052

Comprehensive profiling of mRNA splicing indicates that GC content signals altered cassette exon inclusion in Ewing sarcoma.

Garrett T Graham, Saravana P Selvanathan, Stefan K Zöllner, Emily Stahl, Adam Shlien, Natasha J Caplen, Aykut Üren, Jeffrey A Toretsky.

Ewing sarcoma (EwS) is a small round blue cell tumor and is the second most frequent pediatric bone cancer. 85% of EwS tumors express the fusion oncoprotein EWS-FLI1, the product of a t(11;22) reciprocal translocation. Prior work has indicated that transcription regulation alone does not fully describe the oncogenic capacity of EWS-FLI1, nor does it provide an effective means to stratify patient tumors. Research using EwS cell lines and patient samples has suggested that EWS-FLI1 also disrupts mRNA biogenesis. In this work we both describe the underlying characteristics of mRNA that are aberrantly spliced in EwS tumor samples as well as catalogue mRNA splicing events across other pediatric tumor types. Here, we also use short- and long-read sequencing to identify cis-factors that contribute to splicing profiles we observe in Ewing sarcoma. Our analysis suggests that GC content upstream of cassette exons is a defining factor of mRNA splicing in EwS. We also describe specific splicing events that discriminate EwS tumor samples from the assumed cell of origin, human mesenchymal stem cells derived from bone marrow (hMSC-BM). Finally, we identify specific splicing factors PCBP2, RBMX, and SRSF9 by motif enrichment and confirm findings from tumor samples in EwS cell lines.

DOI: https://doi.org/10.1093/narcan/zcab052