Aim: to exploit tissue-specific interactions among thymic epithelial tumor (TETs) cells and extra-domain B fibronectin (ED-B FN). Material and methods: The stromal pattern of ED-B FN expression was investigated through tumor specimen collection and molecular profiling in 11 patients with recurrent TETs enrolled in prospective theragnostic phase I/II trials with Radretumab, an ED-B FN specific recombinant human antibody. Radretumab radioimmunotherapy (R-RIT) was offered to patients who exhibited the target expression. Experiments included immunochemical analysis (ICH), cell cultures, immunophenotypic analysis, Western blot, slot-blot assay, and quantitative RT-PCR of two primary thymoma cultures we obtained from patients’ samples and in the Ty82 cell line. Results: The in vivo scintigraphic demonstration of ED-B FN expression resulted in R-RIT eligibility in 8/11 patients, of which seven were treated. The best observed response was disease stabilization (n = 5/7) with a duration of 4.3 months (range 3–5 months). IHC data confirmed high ED-B FN expression in the peripherical microenvironment rather than in the center of the tumor, which was more abundant in B3 thymomas. Further, there was a predominant expression of ED-B FN by the stromal cells of the thymoma microenvironment rather than the epithelial cells. Conclusions: Our data support the hypothesis that thymomas induce stromal cells to shift FN production to the ED-B subtype, likely representing a favorable hallmark for tumor progression and metastasis. Collectively, results derived from clinical experience and molecular insights of the in vitro experiments suggested that R-RIT inefficacy is unlikely related to low target expression in TET, being the mechanism of R-RIT resistance eventually related to patients’ susceptibility (i.e., inherent characteristics), the pattern expression of the target (i.e., at periphery), the biological characteristics of the tumor (i.e., aggressive and resistant phenotypes), and/or to format of the target agent (i.e., 131I-L19-SIP).

Thymic epithelial tumors, comprising thymic carcinomas and thymomas, are rare neoplasms. They differ in histology, prognosis, and association with autoimmune diseases such as myasthenia gravis. Thymomas, but not thymic carcinomas, often harbor GTF2I mutations. Mutations of CDKN2A, TP53, and CDKN2B are the most common thymic carcinomas. The acquisition of mutations in genes that control chromatin modifications and epigenetic regulation occurs in the advanced stages of thymic carcinomas. Anti-angiogenic drugs and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have shown promising results for the treatment of unresectable tumors. Since thymic carcinomas are frankly aggressive tumors, this report presents insights into their oncogenic drivers, categorized under the established hallmarks of cancer.

Thymic epithelial cells participate in the maturation and selection of T lymphocytes. This review explores recent insights from single-cell sequencing regarding classifying thymic epithelial cells in both normal and neoplastic thymus. Cortical thymic epithelial cells facilitate thymocyte differentiation and contribute to positive selection. Medullary epithelial cells are distinguished by their expression of AIRE. Cells progress from a pre-AIRE state, containing precursors with cortical and medullary characteristics, termed junctional cells. Mature medullary epithelial cells exhibit promiscuous gene expression and after that downregulate AIRE mRNA. Post-AIRE cells can adopt a Hassall corpuscle-like phenotype or exhibit distinctive differentiation characteristics including tuft cells, ionocytes, neuroendocrine cells, and myoid cells.

Background: Mesangiogenic Progenitor cells (MPCs) were first described in 2008 in cultures of human bone marrow mononuclear cells (hBM-MNCs) aimed at isolating mesenchymal stromal cells (MSCs) using human autologous serum. A selective culture method was subsequently developed to isolate MPCs with a high degree of purity, yielding approximately 1% of the total plated cells. Since their initial description, MPCs have demonstrated the ability to differentiate into highly clonogenic MSCs while retaining early vasculogenic potential. Gene expression profiling of MPCs revealed constitutive expression of pluripotency-associated transcription factors such as OCT-4 and NANOG, as well as SOX15 instead of SOX2, suggesting a possible molecular mechanism that sustains MPC plasticity, defined as the “adult Oct-4 circuit”. Although the expression of these pluripotency-associated markers has been hypothesized to represent a distinctive adult molecular circuit, concerns regarding the tumorigenic potential of MPCs are reasonable and have not yet explored. Methods: Here, we present data from the tumorigenicity test in partial compliance with WHO recommendations of two different MPC-derived cell products in athymic nude mice. Results: Histomorphometric analysis of nodules excised from animals at 6, 8, or 12 weeks post-cell transplantation excluded tumor formation and demonstrated the ability of MPCs to generate homogeneous and organized tissue through distinct phases: an “early” vasculogenic phase, followed by remodeling of the newly formed microvascular network and the deposition of structured, aligned collagen fibers. Conclusions: MPCs do not possess intrinsic tumorigenic potential and spontaneously form vascularized xenogenic tissue four weeks after injection into the subcutaneous space.