bims-myxlip 2022-06-26 papers

Issue of 2022–06–26
three papers selected by
Laura Mannarino, Humanitas Research

Biomedicines. 2022 Jun 05. pii: 1325. [Epub ahead of print]10(6):

Epigenetic and Transcriptional Signaling in Ewing Sarcoma-Disease Etiology and Therapeutic Opportunities.

Ewing sarcoma (EwS), a type of bone and soft tissue tumor, is mainly driven by the expression of the fusion protein EWSR1-FLI1. Upon binding to chromatin, EWSR1-FLI1 reprograms the epigenetic state, alters gene expression, and thus leads to tumorigenesis. Considerable studies have investigated the epigenomic and transcriptomic profiling of EwS. Nevertheless, a comprehensive view of therapeutic targets is still lacking. This review discusses the epigenetic and transcriptional alterations reported in EwS. Specifically, we discuss the binding characteristics of EWSR1-FLI1 on chromatin, the mechanisms of EWSR1-FLI1 in reprograming epigenome, and EWSR1-FLI1-induced transcriptional alterations. Moreover, we summarize the chemical, RNAi, and CRISPR-cas9 high throughput screens conducted in EwS with the goal of assisting in the development of novel therapies to treat this aggressive disease.

Keywords: EWS-FLI1; EWSR1-FLI1; Ewing sarcoma; epigenetic regulation; functional genomic screens; fusion protein; high throughput screens; transcriptional regulation

DOI: https://doi.org/10.3390/biomedicines10061325

ACS Omega. 2022 Jun 14. 7(23): 19243-19260

Exploration of Potential Ewing Sarcoma Drugs from FDA-Approved Pharmaceuticals through Computational Drug Repositioning, Pharmacogenomics, Molecular Docking, and MD Simulation Studies.

Mubashir Hassan, Muhammad Yasir, Saba Shahzadi, Andrzej Kloczkowski.

Novel drug development is a time-consuming process with relatively high debilitating costs. To overcome this problem, computational drug repositioning approaches are being used to predict the possible therapeutic scaffolds against different diseases. In the current study, computational drug repositioning approaches were employed to fetch the promising drugs from the pool of FDA-approved drugs against Ewing sarcoma. The binding interaction patterns and conformational behaviors of screened drugs within the active region of Ewing sarcoma protein (EWS) were confirmed through molecular docking profiles. Furthermore, pharmacogenomics analysis was employed to check the possible associations of selected drugs with Ewing sarcoma genes. Moreover, the stability behavior of selected docked complexes (drugs-EWS) was checked by molecular dynamics simulations. Taken together, astemizole, sulfinpyrazone, and pranlukast exhibited a result comparable to pazopanib and can be used as a possible therapeutic agent in the treatment of Ewing sarcoma.

DOI: https://doi.org/10.1021/acsomega.2c00518

Cell Rep. 2022 Jun 21. pii: S2211-1247(22)00763-X. [Epub ahead of print]39(12): 110977

Single-cell RNA-seq of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity.

Fernando H G Tessaro, Emily Y Ko, Marco De Simone, Roberta Piras, Marina T Broz, Helen S Goodridge, Bonnie Balzer, Stephen L Shiao, Jlenia Guarnerio.

The standard of care is unsuccessful to treat recurrent and aggressive soft-tissue sarcomas. Interventions aimed at targeting components of the tumor microenvironment have shown promise for many solid tumors yet have been only marginally tested for sarcoma, partly because knowledge of the sarcoma microenvironment composition is limited. We employ single-cell RNA sequencing to characterize the immune composition of an undifferentiated pleiomorphic sarcoma mouse model, showing that macrophages in the sarcoma mass exhibit distinct activation states. Sarcoma cells use the pleiotropic cytokine macrophage migration inhibitory factor (MIF) to interact with macrophages expressing the CD74 receptor to switch macrophages' activation state and pro-tumorigenic potential. Blocking the expression of MIF in sarcoma cells favors the accumulation of macrophages with inflammatory and antigen-presenting profiles, hence reducing tumor growth. These data may pave the way for testing new therapies aimed at re-shaping the sarcoma microenvironment, in combination with the standard of care.

Keywords: CP: Cancer; MIF; UPS; macrophage migration inhibitory factor; sarcoma mouse models; soft tissue sarcoma; tumor inflammation; tumor microenvironment; tumor-associated macrophages; undifferentiated pleiomorphic sarcoma

DOI: https://doi.org/10.1016/j.celrep.2022.110977