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Fusion oncogenes (FOs) are common in many cancer types and are powerful drivers of tumor development. Because their expression is exclusive to cancer cells and their elimination induces cell apoptosis in FO-driven cancers, FOs are attractive therapeutic targets. However, specifically targeting the resulting chimeric products is challenging. Based on CRISPR/Cas9 technology, here we devise a simple, efficient and non-patient-specific gene-editing strategy through targeting of two introns of the genes involved in the rearrangement, allowing for robust disruption of the FO specifically in cancer cells. As a proof-of-concept of its potential, we demonstrate the efficacy of intron-based targeting of transcription factors or tyrosine kinase FOs in reducing tumor burden/mortality in in vivo models. The FO targeting approach presented here might open new horizons for the selective elimination of cancer cells. Fusion oncogenes (FO) are common in cancers, but specific targeting of these chimeric genes are challenging. Here the authors report a CRISPR/Cas9 strategy that targets two intronic regions to disrupt the FOs in cancer cells and show that this approach reduces tumour growth and prolongs survival in animal models of cancer.

The thyroid hormone receptor (TR) is a suppressor of ras -mediated responses. To characterize the receptor domains involved in this function, we analyzed a panel of TRβ1 mutants for their ability to interfere with ras-driven cyclin D1 activation, formation of transformation foci and tumor growth in nude mice. Our results show that the domains and mechanisms responsible for the anti-transforming and anti-tumorigenic actions of the receptor are divergent from those operating in classical T3-dependent transcriptional activation. TRβ1 mutants that do not bind coactivators and do not transactivate retained the capacity of suppressing cellular transformation and tumor growth, whereas selective mutations in the hinge region affecting corepressors recruitment abolished these actions, while preserving ligand-dependent transcription. There was a strict parallelism between anti-transforming activity of the various mutants and their ability to antagonize cyclin D1 stimulation by ras , indicating that transrepression mechanisms may have an important function in suppression of the transforming effects of the oncogene by TRβ1. The inhibitory action of T3 on transformation was further enhanced after over-expression of corepressors, while corepressor depletion by means of small-interference RNA reversed significantly hormonal action. This shows an important functional role of endogenous corepressors in suppression of ras -mediated transformation and tumorigenesis by TRβ1

The thyroid hormone receptor (TR) is a suppressor of ras-mediated responses. To characterize the receptor domains involved in this function, we analyzed a panel of TR beta 1 mutants for their ability to interfere with ras-driven cyclin D1 activation, formation of transformation foci and tumor growth in nude mice. Our results show that the domains and mechanisms responsible for the anti-transforming and anti-tumorigenic actions of the receptor are divergent from those operating in classical T3-dependent transcriptional activation. TR beta 1 mutants that do not bind coactivators and do not transactivate retained the capacity of suppressing cellular transformation and tumor growth, whereas selective mutations in the hinge region affecting corepressors recruitment abolished these actions, while preserving ligand-dependent transcription. There was a strict parallelism between anti-transforming activity of the various mutants and their ability to antagonize cyclin D1 stimulation by ras, indicating that transrepression mechanisms may have an important function in suppression of the transforming effects of the oncogene by TR beta 1. The inhibitory action of T3 on transformation was further enhanced after over-expression of corepressors, while corepressor depletion by means of small-interference RNA reversed significantly hormonal action. This shows an important functional role of endogenous corepressors in suppression of ras-mediated transformation and tumorigenesis by TR beta 1

The thyroid hormone receptor (TR) is a suppressor of ras-mediated responses. To characterize the receptor domains involved in this function, we analyzed a panel of TRβ1 mutants for their ability to interfere with ras-driven cyclin D1 activation, formation of transformation foci and tumor growth in nude mice. Our results show that the domains and mechanisms responsible for the anti-transforming and anti-tumorigenic actions of the receptor are divergent from those operating in classical T3-dependent transcriptional activation. TRβ1 mutants that do not bind coactivators and do not transactivate retained the capacity of suppressing cellular transformation and tumor growth, whereas selective mutations in the hinge region affecting corepressors recruitment abolished these actions, while preserving ligand-dependent transcription. There was a strict parallelism between anti-transforming activity of the various mutants and their ability to antagonize cyclin D1 stimulation by ras, indicating that transrepression mechanisms may have an important function in suppression of the transforming effects of the oncogene by TRβ1. The inhibitory action of T3 on transformation was further enhanced after over-expression of corepressors, while corepressor depletion by means of small-interference RNA reversed significantly hormonal action. This shows an important functional role of endogenous corepressors in suppression of ras-mediated transformation and tumorigenesis by TRβ1. [PUBLICATION ABSTRACT]

Abstract Fruit flies (Diptera: Tephritidae) represent a threat to fruit growing worldwide, mainly the citrus culture, however, biological studies show that fruit flies are not perfectly adapted to this host. This study investigated oviposition of Anastrepha fraterculus (Wiedemann, 1830) and Ceratitis capitata (Wiedemann, 1824) and its relation with the pericarp of citrus fruits. We evaluated the relationship between depth of oviposition of A. fraterculus and C. capitata and epicarp thickness of orange [Citrus sinensis (L.) Osbeck)] ‘Navelina’ and tangerine [C. reticulata (L.)] ‘Clemenules’ and the influence of fruit mesocarp of tangerine ‘Clemenules’ on oviposition of these species. The study was conducted under controlled conditions of temperature (25 ± 2 °C), relative humidity (70 ± 10% RH) and photophase (12 h). A. fraterculus and C. capitata laid their eggs in the flavedo region of orange ‘Navelina’ and between the albedo and flavedo of tangerine ‘Clemenules’. When fruits with mesocarp exposed were offered, there was no oviposition by both fruit fly species. The results show that epicarp thickness of citrus fruits did not influence oviposition of A. fraterculus and C. capitata as oviposition did not occur only in the presence of the mesocarp, suggesting that other factors are involved in oviposition of these species. Resumo As moscas-das-frutas (Diptera: Tephritidae) representam um risco à fruticultura mundial, especialmente na cultura dos citros, entretanto estudos biológicos demonstram que as moscas-das-frutas não estão perfeitamente adaptadas à estes hospedeiros. Este estudo investigou a oviposição de Anastrepha fraterculus (Wiedemann, 1830) e Ceratitis capitata (Wiedemann, 1824) e sua relação com o pericarpo de frutos cítricos. Foi avaliada a relação entre a profundidade de oviposição de A. fraterculus e de C. capitata e a espessura do epicarpo dos frutos de laranjeira [Citrus sinensis (L.) Osbeck)] ‘Navelina’ e tangerineira [C. reticulata (L.)] ‘Clemenules’ e a influência do mesocarpo de frutos de tangerineira ‘Clemenules’ na oviposição destas espécies. O estudo foi conduzido em condições controladas de temperatura (25 ± 2 °C), umidade relativa (70 ± 10%) e fotofase (12 horas). A. fraterculus e C. capitata depositaram ovos no flavedo de frutos de laranjeira ‘Navelina’ e entre o flavedo e o albedo de frutos de tangerineira ‘Clemenules’. Quando oferecido frutos com mesocarpo exposto, não houve oviposição por ambas as espécies de mosca. Os resultados demonstram que a espessura do epicarpo de frutos cítricos não influenciou a oviposição de A. fraterculus e de C. capitata, a qual não ocorreu na presença apenas do mesocarpo, sugerindo que outros fatores estão envolvidos na oviposição por estas espécies.

Dietary mono-unsaturated fatty acids (MUFAs) are linked to longevity in several species. But the mechanisms by which MUFAs extend lifespan remain unclear. Here we show that an organelle network involving lipid droplets and peroxisomes is critical for MUFA-induced longevity in Caenorhabditis elegans . MUFAs upregulate the number of lipid droplets in fat storage tissues. Increased lipid droplet number is necessary for MUFA-induced longevity and predicts remaining lifespan. Lipidomics datasets reveal that MUFAs also modify the ratio of membrane lipids and ether lipids—a signature associated with decreased lipid oxidation. In agreement with this, MUFAs decrease lipid oxidation in middle-aged individuals. Intriguingly, MUFAs upregulate not only lipid droplet number but also peroxisome number. A targeted screen identifies genes involved in the co-regulation of lipid droplets and peroxisomes, and reveals that induction of both organelles is optimal for longevity. Our study uncovers an organelle network involved in lipid homeostasis and lifespan regulation, opening new avenues for interventions to delay aging. Papsdorf et al. show that mono-unsaturated fatty acids extend lifespan of C. elegans through induction of peroxisomes and lipid droplets in fat tissues and of a lipid signature predictive of decreased lipid oxidation.

Hematologists and cancer biology researchers have been pioneers in the research and development of blood-based biomarkers, mostly due to the fact that the primary biological material of analysis in hematology is the blood itself (7,8). [...]this Research Topic has addressed some of the most common questions and pitfalls in the development and application of techniques for liquid biopsy analysis: 1. In: “A Support Vector Machine Based on Liquid Immune Profiling Predicts Major Pathological Response to Chemotherapy Plus Anti-PD-1/PD-L1 as a Neoadjuvant Treatment for Patients With Resectable Non-Small Cell Lung Cancer”,Peng et al.analyzed stage Ib-IIIa NSCLC patients undergoing neoadjuvant chemotherapy plus anti-PD-1/PD-L1 (CAPD) before surgical resection.

Extracellular vesicles, such as exosomes, are important effectors in the formation of tumour-fostering niches. Pigmented melanosomes are now shown to have a relevant role in establishing a tumour niche in primary melanoma by reprogramming dermal fibroblasts into cancer-associated fibroblasts through the transfer of miR-211.

Tumour‐draining lymph nodes (LNs) undergo massive remodelling including expansion of the lymphatic sinuses, a process that has been linked to lymphatic metastasis by creation of a pre‐metastatic niche. However, the signals leading to these changes have not been completely understood. Here, we found that extracellular vesicles (EVs) derived from melanoma cells are rapidly transported by lymphatic vessels to draining LNs, where they selectively interact with lymphatic endothelial cells (LECs) as well as medullary sinus macrophages. Interestingly, uptake of melanoma EVs by LN‐resident LECs was partly dependent on lymphatic VCAM‐1 expression, and induced transcriptional changes as well as proliferation of those cells. Furthermore, melanoma EVs shuttled tumour antigens to LN LECs for cross‐presentation on MHC‐I, resulting in apoptosis induction in antigen‐specific CD8+ T cells. In conclusion, our data identify EV‐mediated melanoma—LN LEC communication as a new pathway involved in tumour progression and tumour immune inhibition, suggesting that EV uptake or effector mechanisms in LECs might represent a new target for melanoma therapy.