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Sarcoma 2.0
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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: closed (31 March 2024) | Viewed by 14436

Special Issue Editor

Dr. Shinji Miwa

E-Mail Website
Guest 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

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • sarcoma
  • molecular target
  • therapeutic target

Published Papers (7 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
by Rebecca L. Nance, Xu Wang, Maninder Sandey, Brad M. Matz, AriAnna Thomas and Bruce F. Smith
Int. J. Mol. Sci. 2023, 24(22), 16365; https://doi.org/10.3390/ijms242216365 - 15 Nov 2023
Cited by 1 | Viewed by 1507
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
by Birgit Lohberger, Heike Kaltenegger, Nicole Eck, Dietmar Glänzer, Andreas Leithner and Nadine Kretschmer
Int. J. Mol. Sci. 2023, 24(21), 15910; https://doi.org/10.3390/ijms242115910 - 2 Nov 2023
Viewed by 691
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
by Enrique Fernández-Tabanera, Laura García-García, Carlos Rodríguez-Martín, Saint T. Cervera, Laura González-González, Cristina Robledo, Santiago Josa, Selene Martínez, Luis Chapado, Sara Monzón, Raquel M. Melero-Fernández de Mera and Javier Alonso
Int. J. Mol. Sci. 2023, 24(14), 11774; https://doi.org/10.3390/ijms241411774 - 21 Jul 2023
Cited by 1 | Viewed by 1362
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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17 pages, 3114 KiB  
Article
Platinum-Based Regimens Are Active in Advanced Pediatric-Type Rhabdomyosarcoma in Adults and Depending on HMGB1 Expression
by Nadia Hindi, Jaime Carrillo-García, Elena Blanco-Alcaina, Marta Renshaw, Pablo Luna, José Durán, Natalia Jiménez, Pilar Sancho, Rafael Ramos, David S. Moura and Javier Martín-Broto
Int. J. Mol. Sci. 2023, 24(1), 856; https://doi.org/10.3390/ijms24010856 - 3 Jan 2023
Cited by 4 | Viewed by 2009
Abstract
Rhabdomyosarcoma (RMS) in adults is a rare and aggressive disease, which lacks standard therapies for relapsed or advanced disease. This retrospective study aimed to describe the activity of BOMP-EPI (bleomycin, vincristine, methotrexate and cisplatin alternating with etoposide, cisplatin and ifosfamide), an alternative platinum-based [...] Read more.
Rhabdomyosarcoma (RMS) in adults is a rare and aggressive disease, which lacks standard therapies for relapsed or advanced disease. This retrospective study aimed to describe the activity of BOMP-EPI (bleomycin, vincristine, methotrexate and cisplatin alternating with etoposide, cisplatin and ifosfamide), an alternative platinum-based regimen, in adult patients with relapsed/metastatic RMS. In the study, 10 patients with RMS with a median age at diagnosis of 20.8 years and a female/male distribution of 6/4 received a mean of 2.5 cycles of BOMP-EPI. The best RECIST response was a complete response in 1/10 (10%) patients, a partial response in 5/10 (50%), stable disease in 3/10 (30%) and progression in 1/10 (10%). With a median follow-up in the alive patients from the start of therapy of 30.5 months (15.7–258), all patients progressed with a median progression-free survival of 8.47 months (95% CI 8.1–8.8), and 7/10 patients died with a median overall survival of 24.7 months (95% CI 13.7–35.6). BOMP-EPI was an active chemotherapy regimen in adults with pediatric-type metastatic RMS, with outcomes in terms of survival that seem superior to what was expected for this poor-prognosis population. Low HMGB1 expression level was identified as a predictive factor of better response to this treatment. Full article
(This article belongs to the Special Issue Sarcoma 2.0)
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Review

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15 pages, 2986 KiB  
Review
Transforming Growth Factor Beta and Alveolar Rhabdomyosarcoma: A Challenge of Tumor Differentiation and Chemotherapy Response
by Bhavya Bhushan, Rosa Iranpour, Amirmohammad Eshtiaghi, Simone C. da Silva Rosa, Benjamin W. Lindsey, Joseph W. Gordon and Saeid Ghavami
Int. J. Mol. Sci. 2024, 25(5), 2791; https://doi.org/10.3390/ijms25052791 - 28 Feb 2024
Viewed by 1262
Abstract
Alveolar rhabdomyosarcoma (ARMS), an invasive subtype of rhabdomyosarcoma (RMS), is associated with chromosomal translocation events resulting in one of two oncogenic fusion genes, PAX3-FOXO1 or PAX7-FOXO1. ARMS patients exhibit an overexpression of the pleiotropic cytokine transforming growth factor beta (TGF-β). This overexpression [...] Read more.
Alveolar rhabdomyosarcoma (ARMS), an invasive subtype of rhabdomyosarcoma (RMS), is associated with chromosomal translocation events resulting in one of two oncogenic fusion genes, PAX3-FOXO1 or PAX7-FOXO1. ARMS patients exhibit an overexpression of the pleiotropic cytokine transforming growth factor beta (TGF-β). This overexpression of TGF-β1 causes an increased expression of a downstream transcription factor called SNAIL, which promotes epithelial to mesenchymal transition (EMT). Overexpression of TGF-β also inhibits myogenic differentiation, making ARMS patients highly resistant to chemotherapy. In this review, we first describe different types of RMS and then focus on ARMS and the impact of TGF-β in this tumor type. We next highlight current chemotherapy strategies, including a combination of the FDA-approved drugs vincristine, actinomycin D, and cyclophosphamide (VAC); cabozantinib; bortezomib; vinorelbine; AZD 1775; and cisplatin. Lastly, we discuss chemotherapy agents that target the differentiation of tumor cells in ARMS, which include all-trans retinoic acid (ATRA) and 5-Azacytidine. Improving our understanding of the role of signaling pathways, such as TGF-β1, in the development of ARMS tumor cells differentiation will help inform more tailored drug administration in the future. Full article
(This article belongs to the Special Issue Sarcoma 2.0)
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26 pages, 3250 KiB  
Review
PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas
by Caterina Mancarella, Andrea Morrione and Katia Scotlandi
Int. J. Mol. Sci. 2023, 24(22), 16346; https://doi.org/10.3390/ijms242216346 - 15 Nov 2023
Cited by 1 | Viewed by 2153
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
by Joon Hyuk Choi and Jae Y. Ro
Int. J. Mol. Sci. 2023, 24(6), 5934; https://doi.org/10.3390/ijms24065934 - 21 Mar 2023
Cited by 2 | Viewed by 4779
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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