Thymic stroma and TFII-I: towards new targeted therapies. Issue 1 (January 2022)

• Record Type: Journal Article
• Authors: Manti, Pierluigi Giuseppe; Trattaro, Sebastiano; Castaldi, Davide; Pezzali, Martina; Spaggiari, Lorenzo; Testa, Giuseppe
• Is Part Of: Trends in molecular medicine. Volume 28:Issue 1(2022)
• Page Start: 67
• Page End: 78
• Publication Date: 2022-01
• Subjects: thymic epithelial tumors (TETs) -- thymic stroma -- TFII-I -- targeted therapy -- autoimmunity; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; Physiology, Pathological -- Periodicals; 572.8
• DOI: 10.1016/j.molmed.2021.10.008
• Languages: English
• ISSNs: 1471-4914

Abstract

Abstract : Thymic epithelial tumors (TETs) have been characterized at the molecular level through bioptic sections and cell lines. Despite these advances, there is a need for a more thorough characterization of the thymic stroma in thymoma, particularly because of the diversity of cell types that populate the tumor and the absence of a healthy thymic counterpart. Recent work on healthy pediatric thymi – both in vitro and at the single-cell level – now sets the stage for new studies on their neoplastic counterparts. Furthermore, general transcription factor IIi ( GTF2I ), a thymoma-specific oncogene, as well as some of its SNPs, are increasingly associated with autoimmune disease, a significant feature of thymomas. We summarize recent discoveries in the field and discuss the development of new targeted therapies. Highlights: Recent advances in the thymic field have made it possible (i) to profile human thymic cells at the RNA single-cell level and (ii) to isolate, propagate, and characterize human epithelial progenitor cells and thymic interstitial cells that can in turn generate functional mini-organs when injected into natural rat decellularized scaffolds. General transcription factor IIi (GTF2I) is a thymoma-specific oncogene, and the GTF2I p.L383H/p.L404H mutation can transform mouse thymic epithelial cells (TECs), leading to the overexpression of soluble growth factors, oncogenes, genes related to the epithelial-to-mesenchymal transition (EMT), and antiapoptotic genes. By contrast, cell adhesion molecules, tumor suppressors, and cell-death inducers are downregulated. Overexpression of GTF2I in 7dup autism spectrum disorder (7dupASD) syndrome results in neurocognitive impairments, but alterations in the thymus are not observed. GTF2I SNPs have been increasingly associated with autoimmune disorders which go hand in hand with thymomas. Several clinical trials have been conducted/are ongoing to identify targeted compounds active in thymomas. However, the best combination to halt thymoma progression has not been established.