bims-myxlip Biomed News
on Myxoid liposarcoma
Issue of 2021–08–08
six papers selected by
Laura Mannarino, Humanitas Research
  1. Mechanisms of responsiveness to and resistance against trabectedin in murine models of human myxoid liposarcoma.
  2. Olaratumab's failure in soft tissue sarcoma.
  3. Unraveling Ewing sarcoma tumorigenesis originating from patient-derived Mesenchymal Stem Cells.
  4. Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma.
  5. The oncogenic transcription factor FUS-CHOP can undergo nuclear liquid-liquid phase separation.
  6. Therapeutic Potential of EWSR1-FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma.
  1. Genomics. 2021 Jul 30. pii: S0888-7543(21)00306-2. [Epub ahead of print]
    Mechanisms of responsiveness to and resistance against trabectedin in murine models of human myxoid liposarcoma.
    Laura Mannarino, Ilaria Craparotta, Sara Ballabio, Roberta Frapolli, Marina Meroni, Ezia Bello, Nicolò Panini, Maurizio Callari, Roberta Sanfilippo, Paolo G Casali, Marta Barisella, Chiara Fabbroni, Sergio Marchini, Maurizio D'Incalci.
      Myxoid liposarcoma (MLPS) is a rare soft-tissue sarcoma characterised by the expression of FUS-DDIT3 chimera. Trabectedin has shown significant clinical anti-tumour activity against MLPS. To characterise the molecular mechanism of trabectedin sensitivity and of resistance against it, we integrated genomic and transcriptomic data from treated mice bearing ML017 or ML017/ET, two patient-derived MLPS xenograft models, sensitive to and resistant against trabectedin, respectively. Longitudinal RNA-Seq analysis of ML017 showed that trabectedin acts mainly as a transcriptional regulator: 15 days after the third dose trabectedin modulates the transcription of 4883 genes involved in processes that sustain adipocyte differentiation. No such differences were observed in ML017/ET. Genomic analysis showed that prolonged treatment causes losses in 4p15.2, 4p16.3 and 17q21.3 cytobands leading to acquired-resistance against the drug. The results dissect the complex mechanism of action of trabectedin and provide the basis for novel combinatorial approaches for the treatment of MLPS that could overcome drug-resistance.
    Keywords:  DNA-Seq; Data integration; Myxoid liposarcoma; PDX; RNA-Seq; Trabectedin
    DOI:  https://doi.org/10.1016/j.ygeno.2021.07.028
  2. Rare Tumors. 2021 ;13 20363613211034115
    Olaratumab's failure in soft tissue sarcoma.
    Maroun Bou Zerdan, Aram H Bidikian, Ibrahim Alameh, Clara El Nakib, Hazem I Assi.
      Soft tissue sarcomas remain one of the rarest malignancies with numerous subtypes that go undiagnosed. The PDGFRα antagonist Olaratumab (Lartruvo) was withdrawn from the market due to disappointing findings in the phase III studies. We share our experience with this medication in a tertiary care center in the Middle East and North Africa region. Monitor the effect of Olaratumab on sarcomas when it was used prior to its withdrawal, and compare our findings with the literature. We performed a retrospective analysis of adult patients with advanced-/metastatic soft tissue sarcomas treated with at least two cycles of Olaratumab at a tertiary care center in Lebanon during the period from January 1, 2017 to December 31, 2018. Fifteen patients were included in the study. The mean age was 49 with a range of 26-75 years. The median duration of the use of Olaratumab was 21.3 months with a range of 7.3-37 months. The average number of number of cycles received per patient was four. Five patients were deceased. Median PFS was 7.87 months (95% CI 5.28-10.45), and mean OS was 12.26 months (95% CI 8.47-16.05) Median OS was 9.8 months (95% CI 6.07-13.53). Olaratumab has been withdrawn from the market, and it is currently being investigated as part of the phase II ANNOUNCE 2 trial. Our experience from a tertiary care center shows results similar to those reported in the literature. The immunogenicity and heterogeneity of soft tissue sarcomas pose a challenge to the treatment of soft tissue sarcomas, but they also allow a wide array of possible management solutions.
    Keywords:  Doxorubicin; MENA; Olaratumab; Soft tissue sarcoma; leiomyosarcoma; liposarcoma
    DOI:  https://doi.org/10.1177/20363613211034115
  3. Cancer Res. 2021 Aug 02. pii: canres.3837.2020. [Epub ahead of print]
    Unraveling Ewing sarcoma tumorigenesis originating from patient-derived Mesenchymal Stem Cells.
    Anna Sole, Sandrine Grossetête, Maxime Heintzé, Loelia Babin, Sakina Zaïdi, Patrick Revy, Benjamin Renouf, Anne De Cian, Carine Giovannangeli, Cécile Pierre-Eugène, Isabelle Janoueix-Lerosey, Lucile Couronné, Sophie Kaltenbach, Mark Tomishima, Maria Jasin, Thomas G P Grünewald, Olivier Delattre, Didier Surdez, Erika Brunet.
      Ewing sarcoma (EwS) is characterized by pathognomonic translocations, most frequently fusing EWSR1 with FLI1. An estimated 30% of EwS tumors also display genetic alterations in STAG2, TP53, or CDKN2A (SPC). Numerous attempts to develop relevant EwS models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic and epigenetic features of EwS. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from an EwS patient. Within this model, SPC alterations strongly favored EwS oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed bona fide features of EwS. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in EwS and other cancers. Collectively, these results demonstrate that bone marrow-derived MSCs are a source of origin for EwS and also provide original experimental models to investigate Ewing sarcomagenesis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3837
  4. Oncogene. 2021 Aug 03.
    Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma.
    Daniel J García-Domínguez, Nabil Hajji, Sara Sánchez-Molina, Elisabet Figuerola-Bou, Rocío M de Pablos, Ana M Espinosa-Oliva, Eduardo Andrés-León, Laura Carmen Terrón-Camero, Rocío Flores-Campos, Guillem Pascual-Pasto, María José Robles, Isidro Machado, Antonio Llombart-Bosch, Giovanna Magagnoli, Katia Scotlandi, Ángel M Carcaboso, Jaume Mora, Enrique de Álava, Lourdes Hontecillas-Prieto.
      Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for patients with EWS.
    DOI:  https://doi.org/10.1038/s41388-021-01974-4
  5. J Cell Sci. 2021 Aug 06. pii: jcs.258578. [Epub ahead of print]
    The oncogenic transcription factor FUS-CHOP can undergo nuclear liquid-liquid phase separation.
    Izzy Owen, Debra Yee, Hala Wyne, Theodora Myrto Perdikari, Victoria Johnson, Jeremy Smyth, Robert Kortum, Nicolas L Fawzi, Frank Shewmaker.
      Myxoid liposarcoma is caused by a chromosomal translocation resulting in a fusion protein comprised of the N-terminus of FUS (fused in sarcoma) and the full-length transcription factor CHOP (CCAAT/Enhancer Binding Protein Homologous Protein). FUS functions in RNA metabolism and CHOP is a stress-induced transcription factor. The FUS-CHOP fusion protein causes unique gene expression and oncogenic transformation. Though it is clear the FUS segment is required for oncogenic transformation, the mechanism of FUS-CHOP-induced transcriptional activation is unknown. Recently, some transcription factors and super enhancers were proposed to undergo liquid-liquid phase separation and form membraneless compartments that recruit transcription machinery to gene promoters. Since phase separation of FUS depends on its N-terminus, transcriptional activation by FUS-CHOP could result from the N-terminus driving nuclear phase transitions. Here, we characterized FUS-CHOP in cells and in vitro, and observed novel phase-separating properties relative to unmodified CHOP. Our data indicate FUS-CHOP forms phase-separated condensates that colocalize with BRD4, a marker of super enhancer condensates. We provide evidence that the FUS-CHOP phase transition is a novel oncogenic mechanism and potential therapeutic target for myxoid liposarcoma.
    Keywords:  CHOP; FUS; Liquid-liquid Phase Separation; Oncogenic Fusion Protein; Transcriptional Activation
    DOI:  https://doi.org/10.1242/jcs.258578
  6. Cancers (Basel). 2021 Jul 27. pii: 3783. [Epub ahead of print]13(15):
    Therapeutic Potential of EWSR1-FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma.
    Saint T Cervera, Carlos Rodríguez-Martín, Enrique Fernández-Tabanera, Raquel M Melero-Fernández de Mera, Matias Morin, Sergio Fernández-Peñalver, Maria Iranzo-Martínez, Jorge Amhih-Cardenas, Laura García-García, Laura González-González, Miguel Angel Moreno-Pelayo, Javier Alonso.
      Ewing sarcoma is an aggressive bone cancer affecting children and young adults. The main molecular hallmark of Ewing sarcoma are chromosomal translocations that produce chimeric oncogenic transcription factors, the most frequent of which is the aberrant transcription factor EWSR1-FLI1. Because this is the principal oncogenic driver of Ewing sarcoma, its inactivation should be the best therapeutic strategy to block tumor growth. In this study, we genetically inactivated EWSR1-FLI1 using CRISPR-Cas9 technology in order to cause permanent gene inactivation. We found that gene editing at the exon 9 of FLI1 was able to block cell proliferation drastically and induce senescence massively in the well-studied Ewing sarcoma cell line A673. In comparison with an extensively used cellular model of EWSR1-FLI1 knockdown (A673/TR/shEF), genetic inactivation was more effective, particularly in its capability to block cell proliferation. In summary, genetic inactivation of EWSR1-FLI1 in A673 Ewing sarcoma cells blocks cell proliferation and induces a senescence phenotype that could be exploited therapeutically. Although efficient and specific in vivo CRISPR-Cas9 editing still presents many challenges today, our data suggest that complete inactivation of EWSR1-FLI1 at the cell level should be considered a therapeutic approach to develop in the future.
    Keywords:  CRISPR/Cas9; EWSR1–FLI1; Ewing sarcoma; cell cycle arrest; gene therapy; senescence
    DOI:  https://doi.org/10.3390/cancers13153783
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