bims-myxlip 2022-03-27 papers

Issue of 2022–03–27
five papers selected by
Laura Mannarino, Humanitas Research

Biomedicines. 2022 Feb 28. pii: 573. [Epub ahead of print]10(3):

Current Status and Future Directions of Immunotherapies in Soft Tissue Sarcomas.

William G J Kerrison, Alexander T J Lee, Khin Thway, Robin L Jones, Paul H Huang.

Immunotherapy in soft tissue sarcoma (STS) has experienced a surge of interest in the past decade, contributing to an expanding number of therapeutic options for this extremely heterogenous group of rare malignancies. Immune checkpoint inhibitors (CPIs) targeting the PD-1 and CTLA-4 axes have demonstrated promising responses in a select number of STS subtypes, including rarer subtypes, such as alveolar soft part sarcoma, SWI/SNF-deficient sarcomas, clear cell sarcoma, and angiosarcoma. Multiple pan-subtype sarcoma trials have facilitated the study of possible predictive biomarkers of the CPI response. It has also become apparent that certain therapies, when combined with CPIs, can enhance response rates, although the specific mechanisms of this possible synergy remain unconfirmed in STS. In addition to CPIs, several other immune targeting agents, including anti-tumour-associated macrophage and antigen-directed therapies, are now under assessment in STS with promising efficacy in some subtypes. In this article, we review the state of the art in immunotherapy in STS, highlighting the pre-clinical and clinical data available for this promising therapeutic strategy.

Keywords: immunotherapy; sarcoma; tissue sarcoma

DOI: https://doi.org/10.3390/biomedicines10030573

Cancers (Basel). 2022 Mar 17. pii: 1537. [Epub ahead of print]14(6):

pncCCND1_B Engages an Inhibitory Protein Network to Downregulate CCND1 Expression upon DNA Damage.

Ramona Palombo, Maria Paola Paronetto.

Promoter-associated noncoding RNAs (pancRNAs) represent a class of noncoding transcripts driven from the promoter region of protein-coding or non-coding genes that operate as cis-acting elements to regulate the expression of the host gene. PancRNAs act by altering the chromatin structure and recruiting transcription regulators. PncCCND1_B is driven by the promoter region of CCND1 and regulates CCND1 expression in Ewing sarcoma through recruitment of a multi-molecular complex composed of the RNA binding protein Sam68 and the DNA/RNA helicase DHX9. In this study, we investigated the regulation of CCND1 expression in Ewing sarcoma cells upon exposure to chemotherapeutic drugs. Pan-inhibitor screening indicated that etoposide, a drug used for Ewing sarcoma treatment, promotes transcription of pncCCND1_B and repression of CCND1 expression. RNA immunoprecipitation experiments showed increased binding of Sam68 to the pncCCND1_B after treatment, despite the significant reduction in DHX9 protein. This effect was associated with the formation of DNA:RNA duplexes at the CCND1 promoter. Furthermore, Sam68 interacted with HDAC1 in etoposide treated cells, thus contributing to chromatin remodeling and epigenetic changes. Interestingly, inhibition of the ATM signaling pathway by KU 55,933 treatment was sufficient to inhibit etoposide-induced Sam68-HDAC1 interaction without rescuing DHX9 expression. In these conditions, the DNA:RNA hybrids persist, thus contributing to the local chromatin inactivation at the CCND1 promoter region. Altogether, our results show an active role of Sam68 in DNA damage signaling and chromatin remodeling on the CCND1 gene by fine-tuning transitions of epigenetic complexes on the CCND1 promoter.

Keywords: CCND1; DNA damage; Ewing sarcoma; Sam68; noncoding RNA

DOI: https://doi.org/10.3390/cancers14061537

JCI Insight. 2022 Mar 22. pii: e152293. [Epub ahead of print]7(6):

WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma.

Rovingaile Kriska M Ponce, Nicholas J Thomas, Nam Q Bui, Tadashi Kondo, Ross A Okimoto.

CIC-DUX4 rearrangements define an aggressive and chemotherapy-insensitive subset of undifferentiated sarcomas. The CIC-DUX4 fusion drives oncogenesis through direct transcriptional upregulation of cell cycle and DNA replication genes. Notably, CIC-DUX4-mediated CCNE1 upregulation compromises the G1/S transition to confer a dependence on the G2/M cell cycle checkpoint. Through an integrative transcriptional and kinase activity screen using patient-derived specimens, we now show that CIC-DUX4 sarcomas depend on the G2/M checkpoint regulator WEE1 as part of an adaptive survival mechanism. Specifically, CIC-DUX4 sarcomas depended on WEE1 activity to limit DNA damage and unscheduled mitotic entry. Consequently, genetic or pharmacologic WEE1 inhibition in vitro and in vivo led to rapid DNA damage-associated apoptotic induction of patient-derived CIC-DUX4 sarcomas. Thus, we identified WEE1 as a vulnerability targetable by therapeutic intervention in CIC-DUX4 sarcomas.

Keywords: Cancer; Oncology

DOI: https://doi.org/10.1172/jci.insight.152293

Biomedicines. 2022 Mar 07. pii: 624. [Epub ahead of print]10(3):

Different HSP90 Inhibitors Exert Divergent Effect on Myxoid Liposarcoma In Vitro and In Vivo.

Christoffer Vannas, Lisa Andersson, Soheila Dolatabadi, Parmida Ranji, Malin Lindén, Emma Jonasson, Anders Ståhlberg, Henrik Fagman, Pierre Åman.

The therapeutic options for patients with relapsed or metastatic myxoid liposarcoma (MLS) remain scarce and there is currently no targeted therapy available. Inhibition of the HSP90 family of chaperones has been suggested as a possible therapeutic option for patients with MLS. However, the clinical effect of different HSP90 inhibitors vary considerably and no comparative study in MLS has been performed. Here, we evaluated the effects of the HSP90 inhibitors 17-DMAG, AUY922 and STA-9090 on MLS cell lines and in an MLS patient-derived xenograft (PDX) model. Albeit all drugs inhibited in vitro growth of MLS cell lines, the in vivo responses were discrepant. Whereas 17-DMAG inhibited tumor growth, AUY922 surprisingly led to increased tumor growth and a more aggressive morphological phenotype. In vitro, 17-DMAG and STA-9090 reduced the activity of the MAPK and PI3K/AKT signaling pathways, whereas AUY922 led to a compensatory upregulation of downstream ERK. Furthermore, all three tested HSP90 inhibitors displayed a synergistic combination effect with trabectidin, but not with doxorubicin. In conclusion, our results indicate that different HSP90 inhibitors, albeit having the same target, can vary significantly in downstream effects and treatment outcomes. These results should be considered before proceeding into clinical trials against MLS or other malignancies.

Keywords: HSP90 inhibition; combination therapy; drug treatment; myxoid liposarcoma; receptor tyrosine kinase signaling

DOI: https://doi.org/10.3390/biomedicines10030624

Int J Gen Med. 2022 ;15 3043-3053

Reduced CCR2 Can Improve the Prognosis of Sarcoma by Remodeling the Tumor Microenvironment.

Baixing Wei, Hao Feng, Han Wu.

Background: The tumor microenvironment (TME) plays a very important role in the development of sarcoma (SARC), but it is still unknown how to effectively regulate the TME.
Aim: Our study aims to identify core molecules that can concurrently regulate immune and stromal cells in TME as potential therapeutic targets.
Methods and Results: We used the ESTIMATE algorithm to score the immune and stromal components of 265 SARC samples and determined that increased immune and stromal components in TME were both associated with poor prognosis in SARC. Next, we identified differential genes that regulate both immune and stromal cells, and identified the core prognostic gene CCR2 through the protein-protein interaction (PPI) network, COX analysis, survival analysis, and GSEA enrichment analysis. Next, we calculated the content of infiltrating immune cells and stromal cells in tumors using the CIBERSORT and xcell algorithms, respectively. Using differential analysis and Spearman correlation analysis, we identified 12 immune cells and 7 stromal cells, including CD4+T cells, CD8+T cells, monocytes, macrophages, dendritic cells, NK cells, mesenchymal stem cells (MSC), Fibroblasts and Endothelial cells, all of which were regulated by CCR2.
Conclusion: Increased immune and stromal cell components were associated with poor prognosis in SARC, and CCR2 had a prognostic role in TME, regulating multiple immune and stromal cells, and was an important target for TME remodeling as well as immunotherapy in SARC.

Keywords: CCR2; immunity; macrophages; stromal cells; tumor microenvironment

DOI: https://doi.org/10.2147/IJGM.S349295