Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program

Resultado clínico; Epitranscriptómica; GliomaClinical outcome; Epitranscriptomics; GliomaResultat clínic; Epitranscriptòmica; GliomaTumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.This work was supported by a European Research Council (ERC) Advanced Grant under the European Community’s Seventh Framework Program (FP7/2007-2013)/ERC Grant Agreement No. 268626—EPINORC project (to M. Esteller), the Ministerio de Economía y Competitividad (MINECO) under Grant No. SAF2014-55000-R (to M. Esteller) and the Instituto de Salud Carlos III (ISCIII), under the FIS PI16/01278 Project (to J. Seoane), the Integrated Project of Excellence no. PIE13/00022 (ONCOPROFILE) (to M. Esteller), CIBER 2016 CB16/12/00312 (CIBERONC) (to M. Esteller), co-financed by the European Development Regional Fund, ‘A way to achieve Europe’ ERDF, the AGAUR—Catalan Government (Project No. 2009SGR1315 and 2014SGR633) (to M. Esteller), the Cellex Foundation (to M. Esteller), Obra Social “La Caixa” (to M. Esteller), the CERCA Program and the Health and Science Departments of the Catalan Government (Generalitat de Catalunya) (to M. Esteller) and a grant from the National Health and Medical Research Council of Australia (APP1061551, to TP). M.W. Boudreau is a member of the NIH Chemistry-Biology Interface Training Program (T32-GM070421)

The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer

TCR repertoire; Breast cancer; Clade mutationsRepertori TCR; Càncer de mama; Mutacions cladeRepertorio TCR; Cáncer de mama; Mutaciones cladoThe detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer

LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy

Càncer; Macròfags associats al tumor: LIF; CD8Cáncer; Macrófagos asociados al tumor; CD8Cancer; Tumor-associated macrophages; CD8Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival

Improving the Management of Endometrial Cancer Patients through the Use of Liquid Biopsy Analyses: A Case Report

Endometrial cancer (EC) is the 4th most common neoplasm of the female genital tract, with 15–20% of patients being of high risk of recurrence which leads to a significant decrease in patient survival. Current therapeutic options for patients with EC are poor, being the combined therapy of carboplatin and paclitaxel the standard of care, with limited efficacy. Therefore, new therapeutic options and better monitoring tools are needed to improve the management of the disease. In the current case report, we showcase the value of liquid biopsy analyses in a microsatellite instability EC patient with initially good prognosis that however underwent rapid progression disease within 6 months post-surgery; through the study of plasma cfDNA/ctDNA dynamics to assess the tumour evolution during treatment, as well as the study of the uterine aspirate as a valuable sample that captures the intra-tumour heterogeneity that allows a comprehensive genomic profiling of the disease to identify potential therapeutic options. Furthermore, preclinical models were generated at the time of tumour progression to assess the efficacy of the identified targeted therapies

Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment

Microambient del càncer; Immunologia tumoralMicroambiente del cáncer; Inmunología tumoralCancer microenvironment; Tumour immunologyBrain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.The study was undertaken with the support of the Fundación Asociación Española contra el Cáncer (AECC), FERO (EDM), Ramón Areces Foundation, Cellex Foundation, BBVA (CAIMI), the ISCIII, FIS (PI16/01278), the Ministerio de Ciencia, Innovación y Universidades (SAF2017-89109-P; AEI/FEDER, UE), the Juan de la Cierva formación fellowship (C.R.-P. and L.E.), Sara Borrell fellowship (E.P-R.). We acknowledge support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Program/Generalitat de Catalunya. We also acknowledge the support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement, and the Co-financing by the Spanish Ministry of Ministry of Science and Innovation with funds from the European Regional Development Fund (ERDF) corresponding to the 2014–2020 Smart Growth Operating Program

Circulating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma

Genètica del càncer; Càncer del SNC; Càncer pediàtricGenética del cáncer; Cáncer del SNC; Cáncer pediátricoCancer genetics; CNS cancer; Paediatric cancerThe molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. However, insufficient tissue sample, the presence of tumour heterogeneity, or disseminated disease can challenge its diagnosis and monitoring. Here, we report that the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) recapitulates the genomic alterations of the tumour and facilitates subgrouping and risk stratification, providing valuable information about diagnosis and prognosis. CSF ctDNA also characterises the intra-tumour genomic heterogeneity identifying small subclones. ctDNA is abundant in the CSF but barely present in plasma and longitudinal analysis of CSF ctDNA allows the study of minimal residual disease, genomic evolution and the characterisation of tumours at recurrence. Ultimately, CSF ctDNA analysis could facilitate the clinical management of medulloblastoma patients and help the design of tailored therapeutic strategies, increasing treatment efficacy while reducing excessive treatment to prevent long-term secondary effects.We would like to thank the patients at the Vall d’Hebron Hospital that were enrolled in the study and their families. The study was undertaken with the support of the Fundación Asociación Española contra el Cáncer (AECC), FERO (EDM), Ramón Areces Foundation, Cellex Foundation, BBVA (CAIMI), the ISCIII, FIS (PI16/01278) and the Juan de la Cierva fellowship (L.E). X.S.P. is supported by Ministerio de Economía y Competitividad (MINECO) SAF2013-45836-R and CIBERONC; A.D.N. is supported by the Department of Education of the Basque Government (grant number PRE_2017_1_0100). We thank CERCA Programme/Generalitat de Catalunya for institutional support

LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy

Càncer; Macròfags associats al tumor: LIF; CD8Cáncer; Macrófagos asociados al tumor; CD8Cancer; Tumor-associated macrophages; CD8Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival

The impact of conversion on the risk of major complication following laparoscopic colonic surgery: an international, multicentre prospective audit.

This is the peer reviewed version of the following article: The and E. S. o. C. c. groups (2018). "The impact of conversion on the risk of major complication following laparoscopic colonic surgery: an international, multicentre prospective audit." Colorectal Disease 20(S6): 69-89., which has been published in final form at https://doi.org/10.1111/codi.14371. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.BACKGROUND: Laparoscopy has now been implemented as a standard of care for elective colonic resection around the world. During the adoption period, studies showed that conversion may be detrimental to patients, with poorer outcomes than both laparoscopic completed or planned open surgery. The primary aim of this study was to determine whether laparoscopic conversion was associated with a higher major complication rate than planned open surgery in contemporary, international practice. METHODS: Combined analysis of the European Society of Coloproctology 2017 and 2015 audits. Patients were included if they underwent elective resection of a colonic segment from the caecum to the rectosigmoid junction with primary anastomosis. The primary outcome measure was the 30-day major complication rate, defined as Clavien-Dindo grade III-V. RESULTS: Of 3980 patients, 64% (2561/3980) underwent laparoscopic surgery and a laparoscopic conversion rate of 14% (359/2561). The major complication rate was highest after open surgery (laparoscopic 7.4%, converted 9.7%, open 11.6%, P < 0.001). After case mix adjustment in a multilevel model, only planned open (and not laparoscopic converted) surgery was associated with increased major complications in comparison to laparoscopic surgery (OR 1.64, 1.27-2.11, P < 0.001). CONCLUSIONS: Appropriate laparoscopic conversion should not be considered a treatment failure in modern practice. Conversion does not appear to place patients at increased risk of complications vs planned open surgery, supporting broadening of selection criteria for attempted laparoscopy in elective colonic resection