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Lineage dedifferentiation toward a mesenchymal-like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti-fibrotic drug nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy, and delay tumor relapse in a preclinical model of melanoma. Acquisition of this resistant phenotype and its reversion by nintedanib pointed to miR-143/-145 pro-fibrotic cluster as a driver of this mesenchymal-like phenotype. Upregulation of the miR-143/-145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR-143-3p and miR-145-5p, collaborated to mediate transition toward a drug-resistant undifferentiated mesenchymal-like state by targeting Fascin actin-bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA-mediated regulatory network that contributes to non-genetic adaptive drug resistance and provides proof of principle that preventing MAPKi-induced pro-fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.

Aims DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. Patients and methods DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. Results Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. Conclusions DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.

Background: Scientific results as presented at conferences need to be published in journals so that the scientific community can become aware of the results. The aim of our study was to analyze the peer-review publication rate of abstracts presented at two German Cancer Congresses, based on various factors.Methods: We investigated 1,086 abstracts published by the German Cancer Congress in 2000 and 2010 in relation to the publication in peer-reviewed journals (PubMed publication) within the subsequent 6 years. Furthermore, we studied potential determinants of PubMed publications. For statistical analysis we used Kaplan-Meier estimates and Cox regression (hazard ratios, HR, and 95% confidence intervals).Results: Overall 456 abstracts (42%) were published as PubMed publications, 86 (8%) before the congresses and 370 (34%) after the congresses. The median time to PubMed publication was 16.2 months among 370 post-published abstracts. Abstracts presented as oral presentations had a shorter time to PubMed publication than abstracts presented as posters (14.2 months vs. 16.8 months respectively). In comparison to cell experiments, randomized controlled trials and animal experiments had a higher PubMed publication rate (HR=2.2, 95%CI 1.4-3.4 and HR=2.6, 95%CI 1.6-4.4 respectively). In comparison to abstracts including work in progress, abstracts that included finalized study results had a higher publication rate (HR=1.6, 95%CI 1.2-2.3).Discussion: Our study is the largest study of oncology congresses examining the publication rates and associated determinants. The publication rate was similar to other congresses. There is a considerable potential of publication bias as 58% of congress abstracts were not followed by a peer-reviewed full paper publication within 6 years., Hintergrund: Die auf Konferenzen präsentierten wissenschaftlichen Ergebnisse müssen in Fachzeitschriften veröffentlicht werden, damit das wissenschaftliche Fachpublikum über die Ergebnisse informiert wird. Ziel unserer Studie war es, Abstracts, die auf zwei Deutschen Krebskongressen präsentiert wurden, auf die Wahrscheinlichkeit ihrer anschließenden Peer-Review-Publikation und mögliche Einflussfaktoren hin zu analysieren.Methoden: Wir haben 1.086 Abstracts in Bezug auf ihre Veröffentlichung in Journalen mit Peer-Review-Verfahren (PubMed-Publikation) innerhalb der folgenden 6 Jahre nach ihrer Präsentation auf dem Deutschen Krebskongress in den Jahren 2000 und 2010 untersucht. Darüber hinaus untersuchten wir mögliche Determinanten für PubMed-Publikationen. Für die statistische Analyse verwendeten wir Kaplan-Meier-Schätzungen und die Cox-Regression (Hazard Ratios, HR und 95%-Konfidenzintervalle).Ergebnisse: Insgesamt wurden 456 Abstracts (42%) als PubMed-Publikationen veröffentlicht, 86 (8%) vor den Kongressen und 370 (34%) nach den Kongressen. Im Median betrug die Zeit bis zur Veröffentlichung von PubMed-Publikationen 16,2 Monate. Abstracts, die als Vortrag präsentiert wurden, wurden schneller als PubMed-Publikation veröffentlicht als Abstracts, die als Poster präsentiert wurden (14,2 Monate vs. 16,8 Monaten). Randomisierte kontrollierte Studien und Tierversuche wiesen im Vergleich zu Zellexperimenten eine höhere PubMed-Publikationsrate auf (HR=2,2, 95%CI 1,4-3,4 bzw. HR=2,6, 95%CI 1,6-4,4). Im Vergleich zu Abstracts, die noch laufende Untersuchungen beinhalteten, war die Veröffentlichungsrate bei denjenigen Abstracts mit abgeschlossene Studienergebnissen höher (HR=1,6, 95%CI 1,2-2,3).Diskussion: Unsere Studie ist die größte Studie zu onkologischen Kongressen, in der die Publikationsraten und die damit verbundenen Determinanten untersucht werden. Die Publikationsrate glich der anderer Kongresse. Die Publikationsneigung weist allerdings noch ein erhebliches Potenzial a