Anti-LY6E monoclonal antibody Made to order

Cholangiocarcinoma (CCA) is a deadly cancer worldwide associated with limited therapeutic options. A recent study published in Clinical Science by Wang and colleagues [Clin. Sci. (2019) 133(18), 1935-1953] brought new perspectives to CCA management and therapy by focusing on circular RNAs (circRNAs). CircRNAs belong to an emerging class of functional non-coding RNAs (ncRNAs) regulating numerous biological processes. Notably, circRNAs have been associated with cancer onset and progression, although reports in CCA are very limited so far. In this work, the expression of circular RNA circ-0000284 (aka circHIPK3) was specifically elevated in CCA cell lines, human tumor tissues and plasma exosomes. Gain and loss of function approaches were performed to better understand the molecular mechanisms regulated by circ-0000284. Notably, the authors evaluated the role of circ-0000284 as amicroRNA (miRNA) sponge. By prediction analysis and functional tests, a direct interaction was demonstrated with miR-637 that targets lymphocyte antigen-6 E (LY6E). Increased expression of circ-0000284 was associated with enhanced migration, invasion and proliferation of CCA cell lines. Interestingly, exosomal-mediated circ-0000284 was reported to exhibit pro-oncogenic effects on surrounding normal cells. Altogether, these data highlight circRNAs not only as new players in CCA pathogenesis but also as promising molecules for innovative non-invasive biomarkers, as circRNAs are enriched and stable in exosomes. Further investigations on extracellular vesicles should provide the necessary tools to improve CCA diagnosis, and move toward targeted-therapies.

Although gene therapy can cure patients with severe combined immunodeficiency (SCID) syndromes, the clinical occurrence of T cell malignancies due to insertional mutagenesis has raised concerns about the safety of gene therapy. Several key questions have remained unanswered: (i) are there unique risk factors for X-linked SCID (XSCID) gene therapy that increase the risk of insertional mutagenesis; (it) what other genetic lesions may contribute to transformation; and (iii) what systems can be used to test different vectors for their relative safety? To address these questions, we have developed an XSCID mouse model in which both the Arf tumor-suppressor gene and the gamma c gene were ablated. Gene therapy in this animal model recapitulates the high incidence of integration-dependent, T cell tumors that was seen in the clinical trial. Ligation-mediated PCR analysis showed integration sites near or within established protooncogenes (Chd9, Slamf6, Tde1, Camk2b, and Ly6e), demonstrating that T cell transformation was associated with targeting of oncogene loci; however, no integrations within the Lmo2 locus were identified. The X-SCID background in transplanted cells was required for high rate transformation and was associated with expansion of primitive hematopoietic cells that may serve tumor precursors. This model should be useful for testing safety-modified vectors and for further exploring the risk factors leading to insertional mutagenesis in gene therapy trials.