bims-myxlip 2022-05-15 papers

Issue of 2022–05–15
six papers selected by
Laura Mannarino, Humanitas Research

Mol Cell. 2022 May 04. pii: S1097-2765(22)00382-3. [Epub ahead of print]

Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions.

Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWS::FLI1 in Ewing sarcoma (EwS). Here, we find that EWS::FLI1 induces the robust expression of a specific set of novel spliced and polyadenylated transcripts within otherwise transcriptionally silent regions of the genome. These neogenes (NGs) are virtually undetectable in large collections of normal tissues or non-EwS tumors and can be silenced by CRISPR interference at regulatory EWS::FLI1-bound microsatellites. Ribosome profiling and proteomics further show that some NGs are translated into highly EwS-specific peptides. More generally, we show that hundreds of NGs can be detected in diverse cancers characterized by chimeric TFs. Altogether, this study identifies the transcription, processing, and translation of novel, specific, highly expressed multi-exonic transcripts from otherwise silent regions of the genome as a new activity of aberrant TFs in cancer.

Keywords: chimeric transcription factors; long non-coding RNAs; sarcomas; tumor-specific peptides; tumor-specific transcripts

DOI: https://doi.org/10.1016/j.molcel.2022.04.019

Cancers (Basel). 2022 May 08. pii: 2327. [Epub ahead of print]14(9):

Upregulation of the Mevalonate Pathway through EWSR1-FLI1/EGR2 Regulatory Axis Confers Ewing Cells Exquisite Sensitivity to Statins.

Charlie Buchou, Karine Laud-Duval, Wietske van der Ent, Sandrine Grossetête, Sakina Zaidi, Géraldine Gentric, Maxime Corbé, Kévin Müller, Elaine Del Nery, Didier Surdez, Olivier Delattre.

Ewing sarcoma (EwS) is an aggressive primary bone cancer in children and young adults characterized by oncogenic fusions between genes encoding FET-RNA-binding proteins and ETS transcription factors, the most frequent fusion being EWSR1-FLI1. We show that EGR2, an Ewing-susceptibility gene and an essential direct target of EWSR1-FLI1, directly regulates the transcription of genes encoding key enzymes of the mevalonate (MVA) pathway. Consequently, Ewing sarcoma is one of the tumors that expresses the highest levels of mevalonate pathway genes. Moreover, genome-wide screens indicate that MVA pathway genes constitute major dependencies of Ewing cells. Accordingly, the statin inhibitors of HMG-CoA-reductase, a rate-limiting enzyme of the MVA pathway, demonstrate cytotoxicity in EwS. Statins induce increased ROS and lipid peroxidation levels, as well as decreased membrane localization of prenylated proteins, such as small GTP proteins. These metabolic effects lead to an alteration in the dynamics of S-phase progression and to apoptosis. Statin-induced effects can be rescued by downstream products of the MVA pathway. Finally, we further show that statins impair tumor growth in different Ewing PDX models. Altogether, the data show that statins, which are off-patent, well-tolerated, and inexpensive compounds, should be strongly considered in the therapeutic arsenal against this deadly childhood disease.

Keywords: Ewing sarcoma; MVA pathway; new therapeutic strategy; statin

DOI: https://doi.org/10.3390/cancers14092327

Am J Cancer Res. 2022 ;12(4): 1577-1592

ATR inhibition sensitizes liposarcoma to doxorubicin by increasing DNA damage.

Juncheng Cui, Dylan Dean, Francis J Hornicek, Raphael E Pollock, Robert M Hoffman, Zhenfeng Duan.

Liposarcomas account for approximately 20% of all adult sarcomas and have limited therapeutic options outside of surgery. Inhibition of ataxia-telangiectasia and Rad3 related protein kinase (ATR) has emerged as a promising chemotherapeutic strategy in various cancers. However, its activation, expression, and function in liposarcoma remain unkown. In this study, we investigated the expression, function, and potential of ATR as a therapeutic target in liposarcoma. Activation and expression of ATR in liposarcoma was analyzed by immunohistochemistry, which was further explored for correlation with patient clinical characteristics. ATR-specific siRNA and the ATR inhibitor VE-822 were applied to determine the effect of ATR inhibition on liposarcoma cell proliferation and anti-apoptotic activity. Migration activity and clonogenicity were examined using wound healing and clonogenic assays. ATR (p-ATR) was overexpressed in 88.1% of the liposarcoma specimens and correlated with shorter overall survival in patients. Knockdown of ATR via specific siRNA or inhibition with VE-822 suppressed liposarcoma cell growth, proliferation, migration, colony-forming ability, and spheroid growth. Importantly, ATR inhibition significantly and synergistically enhanced liposarcoma cell line chemosensitivity to doxorubicin. Our findings support ATR as critical to liposarcoma proliferation and doxorubicin resistance. Therefore, the addition of ATR inhibition to a standard doxorubicin regimen is a potential treatment strategy for liposarcoma.

Keywords: ATR; VE-822; liposarcoma; prognostic marker; therapeutic target

Cancer. 2022 May 13.

First-line chemotherapy in advanced intrabdominal well-differentiated/dedifferentiated liposarcoma: An EORTC Soft Tissue and Bone Sarcoma Group retrospective analysis.

Silvia Stacchiotti, Winette T A Van der Graaf, Roberta G Sanfilippo, Sandrine I Marreaud, Winan J Van Houdt, Ian R Judson, Alessandro Gronchi, Hans Gelderblom, Saskia Litiere, Bernd Kasper.

BACKGROUND: No prospective trial with anthracycline-based chemotherapy has individually assessed response in a well-differentiated (WD)/dedifferentiated (DD) liposarcoma patient cohort. We conducted a retrospective analysis of first-line chemotherapy in liposarcoma of intra-abdominal origin (IA-LPS) in patients who had entered the European Organisation for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG) trials.
METHODS: We searched for all adult patients treated with first-line chemotherapy for advanced IA-LPS in the EORTC STBSG phase 2 and 3 trials from 1978. Treatment was aggregated into 5 groups: anthracycline alone, ifosfamide alone, doxorubicin plus ifosfamide (D+IFO), doxorubicin/cyclophosphamide/vincristine/dacarbazine, and "other" (brostallicin, trabectedin). Response was assessed prospectively by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method.
RESULTS: A total of 109 patients with IA-LPS from 13 trials were identified (104 evaluable for response). Overall, there were 10/109 (9.2%) responders: 3/48 (6.3%) in the anthracycline alone group, 2/15 (13%) in the ifosfamide alone group, and 4/18 (22%) in the D+IFO group. At the 10-month median follow-up (interquartile range, 6-24), the median OS was 19 months (95% CI, 15-21) and median PFS 4 months (95% CI, 3-6). D+IFO achieved a not statistically significant longer median PFS (12 months) and median OS (31 months) than observed with other regimens. Univariate/multivariate analysis did not identify prognostic factors.
CONCLUSIONS: Cytotoxic chemotherapy, in particular anthracycline alone, had marginal activity in advanced IA-LPS. Ifosfamide-containing regimens showed higher activity, although it was not statistically significant and in a small number of cases, with the combination of doxorubicin and ifosfamide appearing to be the more active regimen available in fit patients. This series provides a benchmark for future trials on new drugs in WD/DD liposarcoma.

Keywords: anthracycline; chemotherapy; doxorubicin; epirubicin; ifosfamide; liposarcoma; sarcoma

DOI: https://doi.org/10.1002/cncr.34264

Oral Oncol. 2022 May 04. pii: S1368-8375(22)00189-0. [Epub ahead of print]129 105900

Myxoid liposarcoma metastatic to the mandible: First case report and review of the literature.

Kyu-Young Oh, Seong-Doo Hong.

Unlike other soft tissue sarcomas, myxoid liposarcoma tends to metastasize to bone even before developing lung metastases. In this report, we present a unique case of myxoid liposarcoma metastatic to the mandible. A 40-year-old male who had a history of myxoid liposarcoma in the buttock presented with paresthesia in the left lower face and mandible. Radiographic examination revealed an ill-defined radiolucent lesion with cortical destruction in the left mandibular body and ramus. Histopathological examination showed a mixture of small lipoblasts and round primitive mesenchymal cells in a myxoid stroma. Hypercellular areas comprising high-grade round cells were frequently found. The final diagnosis of metastatic myxoid liposarcoma was made. Despite postoperative chemoradiotherapy, further metastases occurred in the lungs and liver, and the patient died of the tumor 23 months after the treatment of the mandibular lesion. This is the first report of myxoid liposarcoma metastatic to the jaw, which may help in the differential diagnosis of intraosseous myxoid tumors of the jaws and highlights unfavorable clinical outcome of metastatic high-grade myxoid liposarcoma.

Keywords: Mandible; Metastasis; Myxoid liposarcoma

DOI: https://doi.org/10.1016/j.oraloncology.2022.105900