bims-myxlip 2022-10-16 papers

Issue of 2022–10–16
three papers selected by
Laura Mannarino, Humanitas Research

Mol Cancer. 2022 Oct 13. 21(1): 199

Neomorphic DNA-binding enables tumor-specific therapeutic gene expression in fusion-addicted childhood sarcoma.

Tilman L B Hölting, Florencia Cidre-Aranaz, Dana Matzek, Bastian Popper, Severin J Jacobi, Cornelius M Funk, Florian H Geyer, Jing Li, Ignazio Piseddu, Bruno L Cadilha, Stephan Ledderose, Jennifer Zwilling, Shunya Ohmura, David Anz, Annette Künkele, Frederick Klauschen, Thomas G P Grünewald, Maximilian M L Knott.

Chimeric fusion transcription factors are oncogenic hallmarks of several devastating cancer entities including pediatric sarcomas, such as Ewing sarcoma (EwS) and alveolar rhabdomyosarcoma (ARMS). Despite their exquisite specificity, these driver oncogenes have been considered largely undruggable due to their lack of enzymatic activity.Here, we show in the EwS model that - capitalizing on neomorphic DNA-binding preferences - the addiction to the respective fusion transcription factor EWSR1-FLI1 can be leveraged to express therapeutic genes.We genetically engineered a de novo enhancer-based, synthetic and highly potent expression cassette that can elicit EWSR1-FLI1-dependent expression of a therapeutic payload as evidenced by episomal and CRISPR-edited genomic reporter assays. Combining in silico screens and immunohistochemistry, we identified GPR64 as a highly specific cell surface antigen for targeted transduction strategies in EwS. Functional experiments demonstrated that anti-GPR64-pseudotyped lentivirus harboring our expression cassette can specifically transduce EwS cells to promote the expression of viral thymidine kinase sensitizing EwS for treatment to otherwise relatively non-toxic (Val)ganciclovir and leading to strong anti-tumorigenic, but no adverse effects in vivo. Further, we prove that similar vector designs can be applied in PAX3-FOXO1-driven ARMS, and to express immunomodulatory cytokines, such as IL-15 and XCL1, in tumor entities typically considered to be immunologically 'cold'.Collectively, these results generated in pediatric sarcomas indicate that exploiting, rather than suppressing, the neomorphic functions of chimeric transcription factors may open inroads to innovative and personalized therapies, and that our highly versatile approach may be translatable to other cancers addicted to oncogenic transcription factors with unique DNA-binding properties.

Keywords: Cancer gene therapy; Ewing sarcoma; Fusion oncogene; GPR64; Rhabdomyosarcoma; Targeted therapy

DOI: https://doi.org/10.1186/s12943-022-01641-6

Cancers (Basel). 2022 Oct 07. pii: 4902. [Epub ahead of print]14(19):

Regulation of Metastasis in Ewing Sarcoma.

Mingli Li, Chunwei Chen.

Ewing sarcoma (EwS) is a type of bone and soft tissue tumor in children and adolescents. Over 85% of cases are caused by the expression of fusion protein EWSR1-FLI1 generated by chromosome translocation. Acting as a potent chimeric oncoprotein, EWSR1-FLI1 binds to chromatin, changes the epigenetic states, and thus alters the expression of a large set of genes. Several studies have revealed that the expression level of EWSR1-FLI1 is variable and dynamic within and across different EwS cell lines and primary tumors, leading to tumoral heterogeneity. Cells with high EWSR1-FLI1 expression (EWSR1-FLI1-high) proliferate in an exponential manner, whereas cells with low EWSR1-FLI1 expression (EWSR1-FLI1-low) tend to have a strong propensity to migrate, invade, and metastasize. Metastasis is the leading cause of cancer-related deaths. The continuous evolution of EwS research has revealed some of the molecular underpinnings of this dissemination process. In this review, we discuss the molecular signatures that contribute to metastasis.

Keywords: EWS-FLI1; EWSR1-FLI1; Ewing sarcoma; fusion protein; heterogeneity; metastasis; prognostic markers

DOI: https://doi.org/10.3390/cancers14194902

Cancers (Basel). 2022 Sep 21. pii: 4578. [Epub ahead of print]14(19):

The Immune Contexture of Liposarcoma and Its Clinical Implications.

Antonia Resag, Giulia Toffanin, Iva Benešová, Luise Müller, Vlatko Potkrajcic, Andrej Ozaniak, Robert Lischke, Jirina Bartunkova, Antonio Rosato, Korinna Jöhrens, Franziska Eckert, Zuzana Strizova, Marc Schmitz.

Liposarcomas (LPS) are the most frequent malignancies in the soft tissue sarcoma family and consist of five distinctive histological subtypes, termed well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. They display variations in genetic alterations, clinical behavior, and prognostic course. While accumulating evidence implicates a crucial role of the tumor immune contexture in shaping the response to anticancer treatments, the immunological landscape of LPS is highly variable across different subtypes. Thus, DDLPS is characterized by a higher abundance of infiltrating T cells, yet the opposite was reported for MLPS. Interestingly, a recent study indicated that the frequency of pre-existing T cells in soft tissue sarcomas has a predictive value for immune checkpoint inhibitor (CPI) therapy. Additionally, B cells and tertiary lymphoid structures were identified as potential biomarkers for the clinical outcome of LPS patients and response to CPI therapy. Furthermore, it was demonstrated that macrophages, predominantly of M2 polarization, are frequently associated with poor prognosis. An improved understanding of the complex LPS immune contexture enables the design and refinement of novel immunotherapeutic approaches. Here, we summarize recent studies focusing on the clinicopathological, genetic, and immunological determinants of LPS.

Keywords: immune architecture; immunotherapy; liposarcoma

DOI: https://doi.org/10.3390/cancers14194578