Ricerc@Sapienza

NKG2D is an activating receptor expressed by NK cells and some subsets of T cells and represents a major recognition receptor for detection and elimination of cancer cells. The ligands of NKG2D are stress-induced self-proteins that can be secreted as soluble molecules by protease-mediated cleavage. The release of NKG2D ligands in the extracellular milieu is considered a mode of finely controlling their surface expression levels and represents a relevant immune evasion mechanism employed by cancer cells to elude NKG2D-mediated immune surveillance.

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes.

It is nowadays widely accepted that some tumors have a niche of cells endowed with stemness features, which may cause resistance to conventional anticancer therapies and relapse/recurrence of the malignancy. These cells are usually referred to as cancer stem cells (CSCs) and, different from normal cancer cells, are rather quiescent. Targeting CSCs is thus a highly challenging but promising strategy to counteract tumor growth, and to develop innovative anticancer agents.

Next-generation sequencing has uncovered novel classes of small RNAs(sRNAs)in eukaryotes,in 30addition to the well-known miRNAs, siRNAs and piRNAs.In particular, sRNAspeciesarise from 31transcription start sites (TSSs) and the transcription termination sites (TTSs) of genes. However, a 32detailed characterization of these new classes of sRNAs is still lacking.

Telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) constitute the core telomerase enzyme that maintains the length of telomeres. Telomere maintenance is affected in a broad range of cancer and degenerative disorders.

Hedgehog signalling (Hh) is a developmental conserved pathway strongly involved in cancers when deregulated. This important pathway is orchestrated by numerous regulators, transduces through distinct routes and is finely tuned at multiple levels. In this regard, ubiquitylation processes stand as essential for controlling Hh pathway output. Although this post-translational modification governs proteins turnover, it is also implicated in non-proteolytic events, thereby regulating the most important cellular functions.

We read with great interest the article “Pathogenetic Analysis of Sinonasal Teratocarcinosarcomas Reveal Actionable ?- Catenin Overexpression and a ?-Catenin Mutation” by Birkeland et al.1 In the article, the authors performed targeted exome sequencing on an index Sinonasal Teratocarcinosarcoma (SNTCS) specimen and identified an activating mutation in the ?-catenin gene (CTNNB1, c.134C > T, p.S45F). In addition, they confirmed ?-catenin overexpression and nuclear localization via immunohistochemistry in the index tumor and in a subsequent case.

Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability.

Di Magno et al. investigate the therapeutic properties of phenformin in Hedgehog-dependent tumors. At clinically relevant doses, phenformin works independent of respiratory complex I through mGPD-mediated increase of the redox state. This promotes CtBP2/Gli1 complex formation and consequent inhibition of Hedgehog transcriptional output and tumor growth.

The Notch signaling pathway plays multiple roles in driving T-cell fate decisions,
proliferation, and aberrant growth. NF-kB is a cell-context key player interconnected
with Notch signaling either in physiological or in pathological conditions. This review
focuses on how themultilayered crosstalk between different Notches and NF-kB subunits
may converge on Foxp3 gene regulation and orchestrate CD4+ regulatory T (Treg)
cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a