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Epigenetic and Transcriptional Networks in Soft Tissue Sarcomas
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Epigenetic and Transcriptional Networks in Soft Tissue Sarcomas

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 January 2023) | Viewed by 13679

Special Issue Editors

Dr. Rossella Rota

E-Mail Website
Guest Editor
Department of Oncohematology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
Interests: Rhabdomyosarcoma; Pediatric soft tissue sarcomas; Epigenetics; Epigenetic drugs; Targeted therapy; Gene transcription; Chromatin modifiers; Diagnostic and prognostic
Dr. Francesco Marampon

E-Mail Website
Guest Editor
Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
Interests: radiotherapy; radio-resistance; rhabdomyosarcoma; adult cancers; epigenetic drugs; targeted therapy; ERK functions; MYC
Special Issues, Collections and Topics in MDPI journals
Dr. Matteo Cassandri

E-Mail Website
Guest Editor
1. Department of Oncohematology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
2. Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
Interests: radiotherapy; rhabdomyosarcoma; epigenetics; transcription regulation; tumor genetics; targeted therapy
Special Issues, Collections and Topics in MDPI journals
Dr. Silvia Pomella

E-Mail Website
Guest Editor
1. Department of Oncohematology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
2. Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
Interests: drug resistance; rhabdomyosarcoma; epigenetics; transcriptional regulation; pharmacogenomics; targeted therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Soft tissue sarcomas (STSs) are a group of rare malignant tumors arising within embryonic mesenchymal tissues giving rise to cartilage, muscle, blood vessels, nerves and fat.

More than 50 subtypes of STSs have been identified, some preferentially affecting children while others affect adults.

STSs are highly heterogeneous at cellular and genomic levels, including subgroups mainly characterized by chromosomal translocations or genomic abnormalities and others with low levels of genomic alteration.

Despite advances in therapeutic approaches over the last several decades, local tumor control is difficult to achieve in aggressive forms and the outcome for metastatic patients still remains poor.

Recent increased knowledge of the primary molecular and genomic mechanisms in different STSs subtypes has often allowed for tumor reclassification, paving the way for the better stratification of patients and innovative targeted therapies.

Furthermore, the advent of new technologies promoted the genome-wide identification of epigenetic and transcriptional alterations associated to STSs subtypes. Altered gene expression driven by epigenetic remodelers and transcriptional regulators has been involved in key biological pathways in STSs. The identification of dysregulations at epigenetic and transcriptional levels that confer therapeutic vulnerabilities is offering novel biomarkers and therapeutic targets that can help in improving clinical management.

This Special Issue welcomes high-quality original research and review articles on basic and translational research focusing on innovative insights into epigenetic and transcriptional regulatory networks in adult and pediatric STSs.

Collectively, these findings may uncover new mechanisms of STSs’ pathogenesis and progression, providing new approaches to improve patient outcome impacting radio and drug resistance.

Dr. Rossella Rota
Prof. Dr. Francesco Marampon
Dr. Matteo Cassandri
Dr. Silvia Pomella
Guest Editors

Manuscript Submission Information

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Keywords

  • soft tissue sarcoma
  • rhabdomyosarcoma
  • synovial sarcoma
  • leiomyosarcoma
  • angiosarcoma
  • fibrosarcoma
  • epithelioid sarcoma
  • gastrointestinal stromal tumor (GIST)
  • liposarcoma
  • malignant peripheral nerve sheath tumor (MPNST)
  • myxofibrosarcoma
  • solitary fibrous tumor
  • undifferentiated (pleomorphic sarcoma)
  • molecular genetics
  • epigenetics
  • transcription factors
  • gene expression
  • miRNA
  • lncRNA
  • histone modifications
  • DNA methylation
  • transcription
  • epigenetic drugs

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Published Papers (4 papers)

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Research

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15 pages, 1467 KiB  
Article
Genomic Profiling of Sarcomas: A Promising Weapon in the Therapeutic Arsenal
by Raquel Lopes-Brás, Dolores Lopez-Presa, Miguel Esperança-Martins, Cecília Melo-Alvim, Lina Gallego, Luís Costa and Isabel Fernandes
Int. J. Mol. Sci. 2022, 23(22), 14227; https://doi.org/10.3390/ijms232214227 - 17 Nov 2022
Cited by 5 | Viewed by 2404
Abstract
Sarcomas are rare malignant mesenchymal neoplasms, and the knowledge of tumor biology and genomics is scarce. Chemotherapy is the standard of care in advanced disease, with poor outcomes. Identifying actionable genomic alterations may offer effective salvage therapeutic options when previous lines have failed. [...] Read more.
Sarcomas are rare malignant mesenchymal neoplasms, and the knowledge of tumor biology and genomics is scarce. Chemotherapy is the standard of care in advanced disease, with poor outcomes. Identifying actionable genomic alterations may offer effective salvage therapeutic options when previous lines have failed. Here, we report a retrospective cohort study of sarcoma patients followed at our center and submitted to comprehensive genomic profiling between January 2020 and June 2021. Thirty patients were included, most (96.7%) with reportable genomic alterations. The most common alterations were linked to cell cycle regulation (TP53, CDKN2A/B, and RB1 deletions and CDK4, MDM2, and MYC amplifications). Most patients (96.7%) had microsatellite stability and low tumor mutational burden (≤10 muts/megabase (Mb); median 2 Muts/Mb). Two-thirds of patients had actionable mutations for targeted treatments, including five cases with alterations amenable to targeted therapies with clinical benefit within the patient’s tumor type, ten cases with targetable alterations with clinical benefit in other tumor types, and five cases with alterations amenable to targeting with drugs under investigation in a clinical trial setting. A significant proportion of cases in this study had actionable genomic alterations with available targeted drugs. Next-generation sequencing is a feasible option for identifying molecular drivers that can provide therapeutic options for individual patients. Molecular Tumor Boards should be implemented in the clinical practice to discuss genomic findings and inform clinically relevant targeted therapies. Full article
(This article belongs to the Special Issue Epigenetic and Transcriptional Networks in Soft Tissue Sarcomas)
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13 pages, 3301 KiB  
Article
Dickkopf-1 Inhibition Reactivates Wnt/β-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo
by Irina Giralt, Gabriel Gallo-Oller, Natalia Navarro, Patricia Zarzosa, Guillem Pons, Ainara Magdaleno, Miguel F. Segura, Constantino Sábado, Raquel Hladun, Diego Arango, José Sánchez de Toledo, Lucas Moreno, Soledad Gallego and Josep Roma
Int. J. Mol. Sci. 2021, 22(23), 12921; https://doi.org/10.3390/ijms222312921 - 29 Nov 2021
Cited by 7 | Viewed by 3006
Abstract
The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the [...] Read more.
The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to β-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression. Full article
(This article belongs to the Special Issue Epigenetic and Transcriptional Networks in Soft Tissue Sarcomas)
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Review

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17 pages, 1848 KiB  
Review
Complex Elucidation of Cells-of-Origin in Pediatric Soft Tissue Sarcoma: From Concepts to Real Life, Hide-and-Seek through Epigenetic and Transcriptional Reprogramming
by Clara Savary, Cécile Picard, Nadège Corradini and Marie Castets
Int. J. Mol. Sci. 2022, 23(11), 6310; https://doi.org/10.3390/ijms23116310 - 4 Jun 2022
Cited by 3 | Viewed by 3422
Abstract
Soft tissue sarcoma (STS) comprise a large group of mesenchymal malignant tumors with heterogeneous cellular morphology, proliferative index, genetic lesions and, more importantly, clinical features. Full elucidation of this wide diversity remains a central question to improve their therapeutic management and the identity [...] Read more.
Soft tissue sarcoma (STS) comprise a large group of mesenchymal malignant tumors with heterogeneous cellular morphology, proliferative index, genetic lesions and, more importantly, clinical features. Full elucidation of this wide diversity remains a central question to improve their therapeutic management and the identity of cell(s)-of-origin from which these tumors arise is part of this enigma. Cellular reprogramming allows transitions of a mature cell between phenotypes, or identities, and represents one key driver of tumoral heterogeneity. Here, we discuss how cellular reprogramming mediated by driver genes in STS can profoundly reshape the molecular and morphological features of a transformed cell and lead to erroneous interpretation of its cell-of-origin. This review questions the fact that the epigenetic context in which a genetic alteration arises has to be taken into account as a key determinant of STS tumor initiation and progression. Retracing the cancer-initiating cell and its clonal evolution, notably via epigenetic approach, appears as a key lever for understanding the origin of these tumors and improving their clinical management. Full article
(This article belongs to the Special Issue Epigenetic and Transcriptional Networks in Soft Tissue Sarcomas)
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13 pages, 819 KiB  
Review
Epigenetics of Cutaneous Sarcoma
by Emi Mashima and Yu Sawada
Int. J. Mol. Sci. 2022, 23(1), 422; https://doi.org/10.3390/ijms23010422 - 31 Dec 2021
Cited by 11 | Viewed by 3700
Abstract
Epigenetic changes influence various physiological and pathological conditions in the human body. Recent advances in epigenetic studies of the skin have led to an appreciation of the importance of epigenetic modifications in skin diseases. Cutaneous sarcomas are intractable skin cancers, and there are [...] Read more.
Epigenetic changes influence various physiological and pathological conditions in the human body. Recent advances in epigenetic studies of the skin have led to an appreciation of the importance of epigenetic modifications in skin diseases. Cutaneous sarcomas are intractable skin cancers, and there are no curative therapeutic options for the advanced forms of cutaneous sarcomas. In this review, we discuss the detailed molecular effects of epigenetic modifications on skin sarcomas, such as dermatofibrosarcoma protuberans, angiosarcoma, Kaposi’s sarcoma, leiomyosarcoma, and liposarcoma. We also discuss the application of epigenetic-targeted therapy for skin sarcomas. Full article
(This article belongs to the Special Issue Epigenetic and Transcriptional Networks in Soft Tissue Sarcomas)
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