bims-myxlip 2022-01-09 papers

Mol Cancer. 2022 Jan 03. 21(1): 1

Integrative gene network and functional analyses identify a prognostically relevant key regulator of metastasis in Ewing sarcoma.

DOI: https://doi.org/10.1186/s12943-021-01470-z

J Control Release. 2021 Dec 30. pii: S0168-3659(21)00688-X. [Epub ahead of print]342 81-92

SPARC-mediated long-term retention of nab-paclitaxel in pediatric sarcomas.

Guillem Pascual-Pasto, Helena Castillo-Ecija, Nora Unceta, Rosario Aschero, Claudia Resa-Pares, Alberto Gómez-Caballero, Monica Vila-Ubach, Oscar Muñoz-Aznar, Mariona Suñol, Victor Burgueño, Soledad Gomez-Gonzalez, Alejandro Sosnik, Manuel Ibarra, Paula Schaiquevich, Enrique de Álava, Oscar M Tirado, Jaume Mora, Angel M Carcaboso.

Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein overexpressed by several cancers. Because SPARC shows high binding affinity to albumin, we reasoned that pediatric sarcoma xenografts expressing SPARC would show enhanced uptake and accumulation of nanoparticle albumin-bound (nab)-paclitaxel, a potent anticancer drug formulation. We first evaluated the expression of SPARC in patient-derived xenografts (PDXs) of Ewing sarcoma, rhabdomyosarcoma and osteosarcoma, finding variable SPARC gene expression that correlated well with SPARC protein measured by immunoblotting. We revealed that the activity of the fusion gene chimera EWSR1-FLI1, the genetic driver of Ewing sarcoma, leads to lower expression of the gene SPARC in these tumors, likely due to enriched acetylation marks of the histone H3 lysine 27 at regions including the SPARC promoter and potential enhancers. Then, we used SPARC-edited Ewing sarcoma cells (A673 line) to demonstrate that SPARC knocked down (KD) cells accumulated significantly less amount of nab-paclitaxel in vitro than SPARC wild type (WT) cells. In vivo, SPARC KD and SPARC WT subcutaneous xenografts in mice achieved similar maximum intratumoral concentrations of nab-paclitaxel, though drug clearance from SPARC WT tumors was significantly slower. We confirmed such SPARC-mediated long-term intratumoral accumulation of nab-paclitaxel in Ewing sarcoma PDX with high expression of SPARC, which accumulated significantly more nab-paclitaxel than SPARC-low PDX. SPARC-high PDX responded better to nab-paclitaxel than SPARC-low tumors, although these results should be taken cautiously, given that the PDXs were established from different patients that could have specific determinants predisposing response to paclitaxel. In addition, SPARC KD Ewing sarcoma xenografts responded better to soluble docetaxel and paclitaxel than to nab-paclitaxel, while SPARC WT ones showed similar response to soluble and albumin-carried drugs. Overall, our results show that pediatric sarcomas expressing SPARC accumulate nab-paclitaxel for longer periods of time, which could have clinical implications for chemotherapy efficacy.

Keywords: Albumin nanoparticles; EWSR1-FLI1; Ewing sarcoma; Nab-paclitaxel; Patient-derived xenograft (PDX); Pediatric solid tumors; Rhabdomyosarcoma; Secreted protein acidic and rich in cysteine (SPARC)

DOI: https://doi.org/10.1016/j.jconrel.2021.12.035

J Exp Clin Cancer Res. 2022 Jan 03. 41(1): 7

Correction to: Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis.

Oxana Schmidt, Nadja Nehls, Carolin Prexler, Kristina von Heyking, Tanja Groll, Katharina Pardon, Heathcliff D Garcia, Tim Hensel, Dennis Gürgen, Anton G Henssen, Angelika Eggert, Katja Steiger, Stefan Burdach, Günther H S Richter.

DOI: https://doi.org/10.1186/s13046-021-02174-4

J Bone Oncol. 2021 Dec;31 100404

One oncogene, several vulnerabilities: EWS/FLI targeted therapies for Ewing sarcoma.

Guillermo Flores, Patrick J Grohar.

EWS/FLI is the defining mutation of Ewing sarcoma. This oncogene drives malignant transformation and progression and occurs in a genetic background characterized by few other recurrent cooperating mutations. In addition, the tumor is absolutely dependent on the continued expression of EWS/FLI to maintain the malignant phenotype. However, EWS/FLI is a transcription factor and therefore a challenging drug target. The difficulty of directly targeting EWS/FLI stems from unique features of this fusion protein as well as the network of interacting proteins required to execute the transcriptional program. This network includes interacting proteins as well as upstream and downstream effectors that together reprogram the epigenome and transcriptome. While the vast number of proteins involved in this process challenge the development of a highly specific inhibitors, they also yield numerous therapeutic opportunities. In this report, we will review how this vast EWS-FLI transcriptional network has been exploited over the last two decades to identify compounds that directly target EWS/FLI and/or associated vulnerabilities.

Keywords: EWS/FLI; Ewing sarcoma; Molecular pharmacology; Transcription factor targeting

DOI: https://doi.org/10.1016/j.jbo.2021.100404

Methods Mol Biol. 2022 ;2435 95-105

Transcriptomic-Assisted Immune and Neoantigen Profiling in Premalignancy.

Kyle Chang, Florencia McAllister, Eduardo Vilar.

Immune-based cancer therapies such as checkpoint inhibitors (CPI) and vaccines have been increasingly studied across different cancer types. Response to such therapies depends on a number of factors such as mutational burden, neoantigen load, presence of tumor infiltrating lymphocytes, among others. Next-generation sequencing (NGS) technologies are particularly attractive to interrogate the immune response compared to traditional assays such as qRT-PCR and immunohistochemistry (IHC) because they enable the discovery of neoantigens and simultaneous profiling of immune infiltration using gene expression on a large scale. Current approaches in immune profiling utilizes whole-exome sequencing (WES) for human leukocyte allele (HLA) typing and neoantigen predictions, and RNA sequencing (RNA-seq) for filtering unexpressed neoantigens and inferring immune infiltration. They have been successfully applied to the tumor setting as there is abundant sample material to perform both experiments. However, premalignant specimens are often much smaller compared to tumors. Therefore, there is a need to explore the viability of adopting a single approach for immune, neoantigen, and mutation profiling. Here, we describe our workflow of using RNA-seq to analyze mutational burden, neoantigen load, and immune expression profile.

Keywords: Immune checkpoints; Mutational rate; Neoantigens; Premalignancy; RNA-seq

DOI: https://doi.org/10.1007/978-1-0716-2014-4_7