METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA

N7-methylguanosine methylation of tRNAs regulates survival to stress in cancer

Tumour progression and therapy tolerance are highly regulated and complex processes largely dependent on the plasticity of cancer cells and their capacity to respond to stress. The higher plasticity of cancer cells highlights the need for identifying targetable molecular pathways that challenge cancer cell survival. Here, we show that

METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N-7-methylguanosine (m(7)G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m(7)G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m(7)G tRNA methylation in cancer cell translation control and tumour biology

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Loss of 7-guanine tRNA methylation affects proliferation, survival and autophagy in Prostate Cancer

Trabajo presentado en el 2nd ASPIC ASEICA International Meeting, celebrado en modalidad virtual del 14 al 15 de octubre de 2021

Deciphering the role of guanine-7 tRNA methylation in Prostate Cancer progression

Trabajo presentado en el Uroncomol Network Meeting , celebrado en modalidad virtual del 6 al 7 de octubre de 2020.Prostate cancer (PCa) is the most prevalent cancer and the third cause of death by cancer in European men. Although most of the patients respond to hormone deprivation therapy, this disease presents a high relapse rate and many patients develop castration resistant prostate cancer (CRPC) with limited treatment options. This progression is due to the existence of preexisting cancer cell sub-populations resistant to conventional treatments and with high capacity to self-renew, leading to tumour regeneration and therapy resistance. Recent evidence has indicated that self-renewal and stress resistance are controlled by epitranscriptomic marks or RNA modifications, and manipulation of the epitranscriptome may be a potential therapeutic target to specifically eliminate those cancer cells resistant to conventional treatments. By using genomic screenings, transcriptomic and epitranscriptomic tools, CRISPR/Cas9 technology, chemistry, proteomics, cell and mouse models and patient samples we aim to decipher the epitranscriptome in prostate cancer in order to implement novel therapeutics strategies to eliminate cancer cells with high survival and self-renewal capacity. The expression of RNA modifying enzymes was analysed in sequencing data from pre-existing studies including TCGA. We found that the transfer-RNA (tRNAs) methyltransferase METTL1 was overexpressed in primary and advanced tumours and increased expression correlated with poor prognosis. Altered expression of the methyltransferase was confirmed by qPCR and WB of primary tumours samples from patients from Basurto University Hospital. In addition, we further confirmed overexpression of the enzyme in a mouse model of PCa, where PTEN is deleted in the prostatic epithelium. For functional characterization of METTL1 role, cells over-expressing, silenced or knocked out for METTL1 using CRISPR/Cas9 were generated in prostate cancer cell lines. In vitro analysis showed that METTL1 overexpression led to enhanced proliferation in adherent and suspension conditions. METTL1 deletion resulted in impaired cell proliferation and migration in prostate cancer cell lines, reduced self-renewal capacity in cell cultures in self-renewal conditions and reduced tumour formation capacity in xenografted models. Mechanistically, METTL1 deletion in cells lead to a reduction of 7-methylguanosine (m7G) in tRNAs and codon usage alterations favouring translation of proteins enriched in m7G-unmethylated codons. Our study concludes that METTL1 is over-expressed in PCa and higher expression correlates with poor prognosis. Depletion of METTL1 leads to a reduction of m7G levels in tRNAs and protein synthesis alterations, which results in a deregulation of essential cellular processes such as proliferation, migration and self-renewal. Whether METTL1 implies a new possible therapeutic approach in PCa treatment needs further evaluation

Post-transcriptional regulation by cytosine-5 methylation of RNA

The recent advent of high-throughput sequencing technologies coupled with RNA modifications detection methods has allowed the detection of RNA modifications at single nucleotide resolution giving a more comprehensive landscape of post-transcriptional gene regulation pathways. In this review, we focus on the occurrence of 5-methylcytosine (m5C) in the transcriptome. We summarise the main findings of the molecular role in post-transcriptional regulation that governs m5C deposition in RNAs. Functionally, m5C deposition can regulate several cellular and physiological processes including development, differentiation and survival to stress stimuli. Despite many aspects concerning m5C deposition in RNA, such as position or sequence context and the fact that many readers and erasers still remain elusive, the overall recent findings indicate that RNA cytosine methylation is a powerful mechanism to post-transcriptionally regulate physiological processes. In addition, mutations in RNA cytosine-5 methyltransferases are associated to pathological processes ranging from neurological syndromes to cancer.R.G-V is a PhD student supported by the Spanish Ministry of Economy and Innovation (MINECO) PhD fellowship (BES-2017-080530). A. S. is a recipient of a Ramón y Cajal contract (RYC-2016-19962). S.B. is a Research Scientist (Científico Titular) of the Spanish Research Council (CSIC) and has been supported by a Ramón y Cajal fellowship for junior investigators (RYC-2014-16550). We acknowledge funding from the Spanish Ministry of Economy and Innovation (MINECO) and Agencia Estatal de Investigación (AEI) and co-financed by the European Development Regional Fund (FEDER) under grant no. SAF2016-78667-R. We thank the Spanish Ministry if Economy and Innovation for the Ochoa Excellence Accreditation of CIC bioGUNE (SEV-2016-0644). We gratefully thank Peter Humphreys for his editorial contribution. S.B.'s institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia cofunded by the Castilla–León autonomous government and the European Regional Development Fund (CLC–2017–01).Peer reviewe

The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues

Recent advancements have illuminated the critical role of RNA modifications in post-transcriptional regulation, shaping the landscape of gene expression. This review explores how tRNA modifications emerge as critical players, fine-tuning functionalities that not only maintain the fidelity of protein synthesis but also dictate gene expression and translation profiles. Highlighting their dysregulation as a common denominator in various cancers, we systematically investigate the intersection of both cytosolic and mitochondrial tRNA modifications with cancer biology. These modifications impact key processes such as cell proliferation, tumorigenesis, migration, metastasis, bioenergetics and the modulation of the tumor immune microenvironment. The recurrence of altered tRNA modification patterns across different cancer types underscores their significance in cancer development, proposing them as potential biomarkers and as actionable targets to disrupt tumorigenic processes, offering new avenues for precision medicine in the battle against cancer.The Spanish Ministry of Science and Innovation [MCIN/AEI/ 10.13039/501100011033] and European Regional Development Fund (ERDF) ‘A way of making Europe’ funded this work [PID2019-111692RB-I00 and PID2022-139598OB-I00]. The Spanish Ministry of Science and Innovation [MCIN/AEI/ 10.13039/501100011033] and European Social Fund ‘Investing in your future’ funded a PhD fellowship to R.G-V. [BES-2017-080530]; USAL-Santander funded a PhD fellowship to A.M.A-G.; and Junta de Castilla y León and Fondo Social Europeo (ESF) funded PhD fellowships to B.M-L. and O.M-G.Peer reviewe

N7-methylguanosine methylation of tRNAs regulates survival to stress in cancer

Tumour progression and therapy tolerance are highly regulated and complex processes largely dependent on the plasticity of cancer cells and their capacity to respond to stress. The higher plasticity of cancer cells highlights the need for identifying targetable molecular pathways that challenge cancer cell survival. Here, we show that N7-guanosine methylation (m7G) of tRNAs, mediated by METTL1, regulates survival to stress conditions in cancer cells. Mechanistically, we find that m7G in tRNAs protects them from stress-induced cleavage and processing into 5’ tRNA fragments. Our analyses reveal that the loss of tRNA m7G methylation activates stress response pathways, sensitising cancer cells to stress. Furthermore, we find that the loss of METTL1 reduces tumour growth and increases cytotoxic stress in vivo. Our study uncovers the role of m7G methylation of tRNAs in stress responses and highlights the potential of targeting METTL1 to sensitise cancer cells to chemotherapy.Ministerio de Ciencia e Innovación SAF2016-78667-R, PID2019-111692RB-I00, PGC2018-096244-B-I00Ministerio de Economía y Competitividad RYC-2014-16550Junta de Castilla y León CSI264P20Consejo Superior de Investigaciones Científicas 2021AEP00

Influence of Gender in Advanced Heart Failure Therapies and Outcome Following Transplantation

Biological differences between males and females change the course of different diseases and affect therapeutic measures' responses. Heart failure is not an exception to these differences. Women account for a minority of patients on the waiting list for heart transplantation or other advanced heart failure therapies. The reason for this under-representation is unknown. Men have a worse cardiovascular risk profile and suffer more often from ischemic heart disease. Conversely, transplanted women are younger and more frequently have non-ischemic cardiac disorders. Women's poorer survival on the waiting list for heart transplantation has been previously described, but this trend has been corrected in recent years. The use of ventricular assist devices in women is progressively increasing, with comparable results than in men. The indication rate for a heart transplant in women (number of women on the waiting list for millions of habitants) has remained unchanged over the past 25 years. Long-term results of heart transplants are equal for both men and women. We have analyzed the data of a national registry of heart transplant patients to look for possible future directions for a more in-depth study of sex differences in this area. We have analyzed 1-year outcomes of heart transplant recipients. We found similar results in men and women and no sex-related interactions with any of the factors related to survival or differences in death causes between men and women. We should keep trying to approach sex differences in prospective studies to confirm if they deserve a different approach, which is not supported by current evidence.Sin financiación6.050 JCR (2020) Q1, 30/141 Cardiac & Cardiovascular Systems1.711 SJR (2020) Q1, 45/349 Cardiology and Cardiovascular MedicineNo data IDR 2019UE