bims-myxlip 2022-02-27 papers

Issue of 2022‒02‒27
two papers selected by
Laura Mannarino
Humanitas Research

Front Oncol. 2022 ;12 816894

FUS-DDIT3 Fusion Oncoprotein Expression Affects JAK-STAT Signaling in Myxoid Liposarcoma.

Soheila Dolatabadi, Emma Jonasson, Lisa Andersson, Manuel Luna Santamaría, Malin Lindén, Tobias Österlund, Pierre Åman, Anders Ståhlberg.

Myxoid liposarcoma is one of the most common sarcoma entities characterized by FET fusion oncogenes. Despite a generally favorable prognosis of myxoid liposarcoma, chemotherapy resistance remains a clinical problem. This cancer stem cell property is associated with JAK-STAT signaling, but the link to the myxoid-liposarcoma-specific FET fusion oncogene FUS-DDIT3 is not known. Here, we show that ectopic expression of FUS-DDIT3 resulted in elevated levels of STAT3 and phosphorylated STAT3. RNA sequencing identified 126 genes that were regulated by both FUS-DDIT3 expression and JAK1/2 inhibition using ruxolitinib. Sixty-six of these genes were connected in a protein interaction network. Fifty-three and 29 of these genes were confirmed as FUS-DDIT3 and STAT3 targets, respectively, using public chromatin immunoprecipitation sequencing data sets. Enriched gene sets among the 126 regulated genes included processes related to cytokine signaling, adipocytokine signaling, and chromatin remodeling. We validated CD44 as a target gene of JAK1/2 inhibition and as a potential cancer stem cell marker in myxoid liposarcoma. Finally, we showed that FUS-DDIT3 interacted with phosphorylated STAT3 in association with subunits of the SWI/SNF chromatin remodeling complex and PRC2 repressive complex. Our data show that the function of FUS-DDIT3 is closely connected to JAK-STAT signaling. Detailed deciphering of molecular mechanisms behind tumor progression opens up new avenues for targeted therapies in sarcomas and leukemia characterized by FET fusion oncogenes.

Keywords: CD44; FET sarcomas; FUS-DDIT3; JAK-STAT signaling; cancer stem cells; myxoid liposarcoma

DOI: https://doi.org/10.3389/fonc.2022.816894

Biomedicines. 2022 Feb 03. pii: 373. [Epub ahead of print]10(2):

HDAC Inhibition for Optimized Cellular Immunotherapy of NY-ESO-1-Positive Soft Tissue Sarcoma.

Wenjie Gong, Lei Wang, Maria-Luisa Schubert, Christian Kleist, Brigitte Neuber, Sanmei Wang, Mingya Yang, Angela Hückelhoven-Krauss, Depei Wu, Anita Schmitt, Carsten Müller-Tidow, Hiroshi Shiku, Michael Schmitt, Leopold Sellner.

Adoptive cell therapy with NY-ESO-1-specific T cells is a promising option for the treatment of soft tissue sarcoma (STS) but achieves only transient tumor control in the majority of cases. A strategy to optimize this cell therapeutic approach might be the modulation of the expression of the cancer-testis antigen NY-ESO-1 using histone deacetylase inhibitors (HDACis). In this study, the ex vivo effect of combining NY-ESO-1-specific T cells with the clinically approved pan HDACis panobinostat or vorionstat was investigated. Our data demonstrated that STS cells were sensitive to HDACis. Administration of HDACi prior to NY-ESO-1-specific T cells exerted enhanced lysis against the NY-ESO-1+ STS cell line SW982. This correlated with an increase in the NY-ESO-1 and HLA-ABC expression of SW982 cells, as well as increased CD25 expression on NY-ESO-1-specific T cells. Furthermore, the immune reactivity of NY-ESO-1-specific CD8+ T cells in terms of cytokine release was enhanced by HDACis. In summary, pretreatment with HDACis represents a potential means of enhancing the cytotoxic efficacy of NY-ESO-1-specific T cells against NY-ESO-1-positive STS.

Keywords: HDAC inhibition; NY-ESO-1-specific T cells; panobinostat; soft tissue sarcoma; vorinostat

DOI: https://doi.org/10.3390/biomedicines10020373