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Molecular, Genetic and Immunomodulatory Mechanisms in Soft Tissue Sarcoma

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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 7254

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Guest Editor
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Milan, Italy

Special Issue Information

Dear Colleagues,

Soft tissue sarcomas (STS) are a heterogeneous group of rare malignant neoplasms arising within embryonic mesenchymal tissues during the process of differentiation into cartilage, muscle, blood vessels, nerves, and fat. Diagnosis of sarcoma is based on morphology, immunohistochemistry, and clinicopathological correlation. A better understanding of the molecular biology of pathogenesis is fundamental, as STSs are distinguished by specific molecular aberrations, such as somatic mutations, deletions, gene amplifications, reciprocal translocations, and complex karyotypes. Molecular studies have been critical in providing refinements to morphologic sarcoma classification, at times very challenging, while contributing to diagnostic information, prognostic stratification and predictive insights concerning specific therapies.

All molecular and genetic discoveries have led to a better understanding of the modern concepts of cancer biology, including molecular signals driving tumor growth and permanence, and the molecular pathways involved leading to treatment strategy options for STS. Sustained growth, the evasion of growth suppressors, resistance to death, induction of angiogenesis, and the ability to invade and spread are fundamental tumor characteristics, all of which have underlying molecular correlates that scientists are beginning to uncover and comprehend. However, in addition to molecular and genetic findings, other determinants, such as genomic instability, immunological profile, tumor-promoting inflammation, and deregulation of cellular energy pathways have a critical role in the aggressiveness of sarcomas. Only 15% of STS patients respond in immunotherapy trials; there are no biomarkers predicting the response of STS to checkpoint blockade therapies yet. Therefore, unraveling immunomodulatory mechanisms in STS have the potential to unveil essential insights to immunotherapy approaches. 

This Special Issue of IJMS intends to bring together high-quality publications covering several innovating insights on the molecular, genetic and immunomodulatory mechanisms, leading to a better understanding of STS development. These novel aspects may ultimately improve the clinical management of both adult and pediatric STS patients, providing a better clinical understanding, developing safer and more potent targeted therapies, and driving new initiatives to improve their final outcome.

Dr. Gasparini Patrizia
Guest Editor

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Keywords

  • soft tissue sarcoma
  • pediatric tumors
  • rhabdomyosarcoma
  • non-rhabdomyosarcoma
  • synovial sarcoma
  • leiomyosarcoma
  • angiosarcoma
  • dermatofibrosarcoma protuberans
  • epithelioid sarcoma
  • gastrointestinal stromal tumor (GIST)
  • leiomyosarcoma
  • liposarcoma
  • malignant peripheral nerve sheath tumor (MPNST)
  • myxofibrosarcoma
  • solitary fibrous tumor
  • undifferentiated (pleomorphic sarcoma)
  • molecular genetics
  • immune profile
  • gene expression
  • miRNA
  • target therapy
  • metastasis
  • pediatric oncology
  • immunotherapy

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Published Papers (2 papers)

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Research

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20 pages, 2643 KiB  
Article
Establishment and Characterization of a Cell Line (S-RMS1) Derived from an Infantile Spindle Cell Rhabdomyosarcoma with SRF-NCOA2 Fusion Transcript
by Marta Colletti, Angela Galardi, Evelina Miele, Virginia Di Paolo, Ida Russo, Cristiano De Stefanis, Rita De Vito, Martina Rinelli, Andrea Ciolfi, Biagio De Angelis, Angelica Zin, Alessandro Guffanti, Maria Cristina Digilio, Antonio Novelli, Rita Alaggio, Giuseppe Maria Milano and Angela Di Giannatale
Int. J. Mol. Sci. 2021, 22(11), 5484; https://doi.org/10.3390/ijms22115484 - 22 May 2021
Cited by 4 | Viewed by 3044
Abstract
Background: Spindle cell rhabdomyosarcoma (S-RMS) is a rare tumor that was previously considered as an uncommon variant of embryonal RMS (ERMS) and recently reclassified as a distinct RMS subtype with NCOA2, NCOA1, and VGLL2 fusion genes. In this study, we established a [...] Read more.
Background: Spindle cell rhabdomyosarcoma (S-RMS) is a rare tumor that was previously considered as an uncommon variant of embryonal RMS (ERMS) and recently reclassified as a distinct RMS subtype with NCOA2, NCOA1, and VGLL2 fusion genes. In this study, we established a cell line (S-RMS1) derived from a four-month-old boy with infantile spindle cell RMS harboring SRF-NCOA2 gene fusion. Methods: Morphological and molecular characteristics of S-RMS1 were analyzed and compared with two RMS cell lines, RH30 and RD18. Whole genome sequencing of S-RMS1 and clinical exome sequencing of genomic DNA were performed. Results: S-RMS1 showed cells small in size, with a fibroblast-like morphology and positivity for MyoD-1, myogenin, desmin, and smooth muscle actin. The population doubling time was 3.7 days. Whole genome sequencing demonstrated that S-RMS1 retained the same genetic profile of the tumor at diagnosis. A Western blot analysis showed downregulation of AKT-p and YAP-p while RT-qPCR showed upregulation of endoglin and GATA6 as well as downregulation of TGFßR1 and Mef2C transcripts. Conclusion: This is the first report of the establishment of a cell line from an infantile spindle cell RMS with SRF-NCOA2 gene fusion. S-RMS1 should represent a useful tool for the molecular characterization of this rare and almost unknown tumor. Full article
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Review

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15 pages, 1044 KiB  
Review
Molecular Determinants of Soft Tissue Sarcoma Immunity: Targets for Immune Intervention
by Marcella Tazzari, Laura Bergamaschi, Alessandro De Vita, Paola Collini, Marta Barisella, Alessia Bertolotti, Toni Ibrahim, Sandro Pasquali, Chiara Castelli and Viviana Vallacchi
Int. J. Mol. Sci. 2021, 22(14), 7518; https://doi.org/10.3390/ijms22147518 - 13 Jul 2021
Cited by 18 | Viewed by 3622
Abstract
Soft tissue sarcomas (STSs) are a family of rare malignant tumors encompassing more than 80 histologies. Current therapies for metastatic STS, a condition that affects roughly half of patients, have limited efficacy, making innovative therapeutic strategies urgently needed. From a molecular point of [...] Read more.
Soft tissue sarcomas (STSs) are a family of rare malignant tumors encompassing more than 80 histologies. Current therapies for metastatic STS, a condition that affects roughly half of patients, have limited efficacy, making innovative therapeutic strategies urgently needed. From a molecular point of view, STSs can be classified as translocation-related and those with a heavily rearranged genotype. Although only the latter display an increased mutational burden, molecular profiles suggestive of an “immune hot” tumor microenvironment are observed across STS histologies, and response to immunotherapy has been reported in both translocation-related and genetic complex STSs. These data reinforce the notion that immunity in STSs is multifaceted and influenced by both genetic and epigenetic determinants. Cumulative evidence indicates that a fine characterization of STSs at different levels is required to identify biomarkers predictive of immunotherapy response and to discover targetable pathways to switch on the immune sensitivity of “immune cold” tumors. In this review, we will summarize recent findings on the interplay between genetic landscape, molecular profiling and immunity in STSs. Immunological and molecular features will be discussed for their prognostic value in selected STS histologies. Finally, the local and systemic immunomodulatory effects of the targeted drugs imatinib and sunitinib will be discussed. Full article
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