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Sarcoma 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 31 March 2024 | Viewed by 8298

Special Issue Editor

Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
Interests: sarcoma; chemotherapy; immunotherapy; biological reconstruction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Due to the rarity and heterogeneity of sarcoma, investigation into molecular targets and new treatments has been particularly challenging. Although intensive chemotherapy and the establishment of surgical procedures have improved the outcomes of patients with sarcomas, the curative rate of recurrent and metastatic sarcomas remains unsatisfactory. Recent basic science research has revealed some of the mechanisms of the progression and metastasis of malignancies, including proliferation, apoptosis, angiogenesis, tumor microenvironment, migration, invasion, and the regulation of antitumor immune systems. On the basis of these basic studies, new anticancer drugs have been developed, and the efficacies and safety of the new drugs have been assessed by clinical trials. This Special Issue aims to bring together the highest-quality original/review articles on basic and clinical research for bone and soft tissue tumors. We invite papers addressing molecular biology, microenvironment, and metastasis mechanisms, as well as those analyzing recent clinical research on new therapeutic approaches.

Dr. Shinji Miwa
Guest Editor

Manuscript Submission Information

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Keywords

  • sarcoma
  • molecular target
  • therapeutic target

Published Papers (5 papers)

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Research

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17 pages, 4711 KiB  
Article
Single-Nuclei Multiome (ATAC + Gene Expression) Sequencing of a Primary Canine Osteosarcoma Elucidates Intra-Tumoral Heterogeneity and Characterizes the Tumor Microenvironment
Int. J. Mol. Sci. 2023, 24(22), 16365; https://doi.org/10.3390/ijms242216365 - 15 Nov 2023
Viewed by 1121
Abstract
Osteosarcoma (OSA) is a highly aggressive bone tumor primarily affecting pediatric or adolescent humans and large-breed dogs. Canine OSA shares striking similarities with its human counterpart, making it an invaluable translational model for uncovering the disease’s complexities and developing novel therapeutic strategies. Tumor [...] Read more.
Osteosarcoma (OSA) is a highly aggressive bone tumor primarily affecting pediatric or adolescent humans and large-breed dogs. Canine OSA shares striking similarities with its human counterpart, making it an invaluable translational model for uncovering the disease’s complexities and developing novel therapeutic strategies. Tumor heterogeneity, a hallmark of OSA, poses significant challenges to effective treatment due to the evolution of diverse cell populations that influence tumor growth, metastasis, and resistance to therapies. In this study, we apply single-nuclei multiome sequencing, encompassing ATAC (Assay for Transposase-Accessible Chromatin) and GEX (Gene Expression, or RNA) sequencing, to a treatment-naïve primary canine osteosarcoma. This comprehensive approach reveals the complexity of the tumor microenvironment by simultaneously capturing the transcriptomic and epigenomic profiles within the same nucleus. Furthermore, these results are analyzed in conjunction with bulk RNA sequencing and differential analysis of the same tumor and patient-matched normal bone. By delving into the intricacies of OSA at this unprecedented level of detail, we aim to unravel the underlying mechanisms driving intra-tumoral heterogeneity, opening new avenues for therapeutic interventions in both human and canine patients. This study pioneers an approach that is broadly applicable, while demonstrating significant heterogeneity in the context of a single individual’s tumor. Full article
(This article belongs to the Special Issue Sarcoma 2.0)
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14 pages, 3830 KiB  
Article
The Biological Assessment of Shikonin and β,β-dimethylacrylshikonin Using a Cellular Myxofibrosarcoma Tumor Heterogeneity Model
Int. J. Mol. Sci. 2023, 24(21), 15910; https://doi.org/10.3390/ijms242115910 - 02 Nov 2023
Viewed by 494
Abstract
Myxofibrosarcoma (MFS) is a subtype of soft tissue sarcoma of connective tissue, which is characterized by large intra-tumor heterogeneity. Therapy includes surgical resection. Additional chemotherapy is of limited effect. In this study, we demonstrated the potent anticancer activity of shikonin derivatives in our [...] Read more.
Myxofibrosarcoma (MFS) is a subtype of soft tissue sarcoma of connective tissue, which is characterized by large intra-tumor heterogeneity. Therapy includes surgical resection. Additional chemotherapy is of limited effect. In this study, we demonstrated the potent anticancer activity of shikonin derivatives in our MFS cellular model of tumor heterogeneity for developing a new therapeutic approach. The impact of shikonin and β,β-dimethylacrylshikonin (DMAS) on viability, apoptotic induction, MAPK phosphorylation, and DNA damage response were analyzed by means of two human MFS cell lines, MUG-Myx2a and MUG-Myx2b, derived from a singular tumor tissue specimen. MFS cells showed a dose-dependent inhibition of cell viability and a significant induction of apoptosis. Treatment with shikonin derivatives caused an inhibition of pSTAT3 and an increase in pAKT, pERK, pJNK, and pp38. DMAS and shikonin inhibited the activation of the two master upstream regulators of the DNA damage response, ATR and ATM. MUG-Myx2b, which contains an additional PTEN mutation, was more sensitive in some targets. These data demonstrate the significant antitumorigenic effect of shikonin derivatives in MFS and highlight the importance of intra-tumor heterogeneity in treatment planning. Full article
(This article belongs to the Special Issue Sarcoma 2.0)
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20 pages, 4286 KiB  
Article
CD44 Modulates Cell Migration and Invasion in Ewing Sarcoma Cells
Int. J. Mol. Sci. 2023, 24(14), 11774; https://doi.org/10.3390/ijms241411774 - 21 Jul 2023
Cited by 1 | Viewed by 1069
Abstract
The chimeric EWSR1::FLI1 transcription factor is the main oncogenic event in Ewing sarcoma. Recently, it has been proposed that EWSR1::FLI1 levels can fluctuate in Ewing sarcoma cells, giving rise to two cell populations. EWSR1::FLI1low cells present a migratory and invasive phenotype, while [...] Read more.
The chimeric EWSR1::FLI1 transcription factor is the main oncogenic event in Ewing sarcoma. Recently, it has been proposed that EWSR1::FLI1 levels can fluctuate in Ewing sarcoma cells, giving rise to two cell populations. EWSR1::FLI1low cells present a migratory and invasive phenotype, while EWSR1::FLI1high cells are more proliferative. In this work, we described how the CD44 standard isoform (CD44s), a transmembrane protein involved in cell adhesion and migration, is overexpressed in the EWSR1::FLI1low phenotype. The functional characterization of CD44s (proliferation, clonogenicity, migration, and invasion ability) was performed in three doxycycline-inducible Ewing sarcoma cell models (A673, MHH-ES1, and CADO-ES1). As a result, CD44s expression reduced cell proliferation in all the cell lines tested without affecting clonogenicity. Additionally, CD44s increased cell migration in A673 and MHH-ES1, without effects in CADO-ES1. As hyaluronan is the main ligand of CD44s, its effect on migration ability was also assessed, showing that high molecular weight hyaluronic acid (HMW-HA) blocked cell migration while low molecular weight hyaluronic acid (LMW-HA) increased it. Invasion ability was correlated with CD44 expression in A673 and MHH-ES1 cell lines. CD44s, upregulated upon EWSR1::FLI1 knockdown, regulates cell migration and invasion in Ewing sarcoma cells. Full article
(This article belongs to the Special Issue Sarcoma 2.0)
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Review

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26 pages, 3250 KiB  
Review
PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas
Int. J. Mol. Sci. 2023, 24(22), 16346; https://doi.org/10.3390/ijms242216346 - 15 Nov 2023
Cited by 1 | Viewed by 1265
Abstract
Sarcomas are heterogeneous bone and soft tissue cancers representing the second most common tumor type in children and adolescents. Histology and genetic profiling discovered more than 100 subtypes, which are characterized by peculiar molecular vulnerabilities. However, limited therapeutic options exist beyond standard therapy [...] Read more.
Sarcomas are heterogeneous bone and soft tissue cancers representing the second most common tumor type in children and adolescents. Histology and genetic profiling discovered more than 100 subtypes, which are characterized by peculiar molecular vulnerabilities. However, limited therapeutic options exist beyond standard therapy and clinical benefits from targeted therapies were observed only in a minority of patients with sarcomas. The rarity of these tumors, paucity of actionable mutations, and limitations in the chemical composition of current targeted therapies hindered the use of these approaches in sarcomas. Targeted protein degradation (TPD) is an innovative pharmacological modality to directly alter protein abundance with promising clinical potential in cancer, even for undruggable proteins. TPD is based on the use of small molecules called degraders or proteolysis-targeting chimeras (PROTACs), which trigger ubiquitin-dependent degradation of protein of interest. In this review, we will discuss major features of PROTAC and PROTAC-derived genetic systems for target validation and cancer treatment and focus on the potential of these approaches to overcome major issues connected to targeted therapies in sarcomas, including drug resistance, target specificity, and undruggable targets. A deeper understanding of these strategies might provide new fuel to drive molecular and personalized medicine to sarcomas. Full article
(This article belongs to the Special Issue Sarcoma 2.0)
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36 pages, 6440 KiB  
Review
The Recent Advances in Molecular Diagnosis of Soft Tissue Tumors
Int. J. Mol. Sci. 2023, 24(6), 5934; https://doi.org/10.3390/ijms24065934 - 21 Mar 2023
Cited by 1 | Viewed by 3819
Abstract
Soft tissue tumors are rare mesenchymal tumors with divergent differentiation. The diagnosis of soft tissue tumors is challenging for pathologists owing to the diversity of tumor types and histological overlap among the tumor entities. Present-day understanding of the molecular pathogenesis of soft tissue [...] Read more.
Soft tissue tumors are rare mesenchymal tumors with divergent differentiation. The diagnosis of soft tissue tumors is challenging for pathologists owing to the diversity of tumor types and histological overlap among the tumor entities. Present-day understanding of the molecular pathogenesis of soft tissue tumors has rapidly increased with the development of molecular genetic techniques (e.g., next-generation sequencing). Additionally, immunohistochemical markers that serve as surrogate markers for recurrent translocations in soft tissue tumors have been developed. This review aims to provide an update on recently described molecular findings and relevant novel immunohistochemical markers in selected soft tissue tumors. Full article
(This article belongs to the Special Issue Sarcoma 2.0)
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