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Objective Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways. Design and Methods Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P <.05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA). Results Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P =.012); 5-year OS of 69.7%, 32.5%, and 27.7% (P =.003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs. Conclusions We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients. [ABSTRACT FROM AUTHOR]

Objective: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways., Design and Methods: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA)., Results: Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs., Conclusions: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients., Competing Interests: Conflict of interest: J.C. has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA, Advanz Pharma, Amgen, Bayer, Esteve, Hutchmed, Ipsen, Merck, Novartis, Roche, Sanofi, Lilly, Eisai, Bayer, and ITM, and has received research support from Pfizer, Novartis, Astrazeneca, Eisai, AAA, Amgen, Bayer, Roche, Gilead, and ITM. M.B. reports Advisory from Novartis, Ipsen, and Pfizer. P.J.-F. has received speaker honoraria or consultant honoraria from Adacap, Astellas, BMS, Lilly, and MSD. D.C. has provided scientific advice and/or received honoraria or funding for continuous medical education from Janssen Oncology, Roche/Genetech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, BMS, MSD, Bayer, Lilly, Sanofi, Pierre Fabre, and Boerhinger. F.S. has received honoraria for medical education and research activity from Ipsen, Novartis, Pfizer, Advanced Accelerator Applications, MSD/Merck, and Hutchmed. A.T. has provided scientific advice and/or received honoraria from ADACAP, Ipsen, Novartis, and Pfizer. R.G.-C. has provided scientific advice and/or received honoraria or funding for continuous medical education from ADACAP, Advanz Pharma, Amgen, Bayer, BMS, Boerhinger, Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pierre Fabre, Roche, Servier, and Sanofi, and has received research support from Pfizer, BMS, and MSD. The remaining authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

To survive under water deficiency, plants alter gene expression patterns, make structural and physiological adjustments, and optimize the use of water. Rapid degradation and turnover of proteins is required for effective nutrient recycling. Here, we examined the transcriptional responses of the C1A cysteine protease family to drought in barley and found that four genes were up-regulated in stressed plants. Knock-down lines for the protease-encoding genes HvPap-1 and HvPap-19 showed unexpected changes in leaf cuticle thickness and stomatal pore area. The efficiency of photosystem II and the total amount of proteins were almost unaltered in stressed transgenic plants while both parameters decreased in stressed wild-type plants. Although the patterns of proteolytic activities in the knock-down lines did not change, the amino acid accumulation increased in response to drought, concomitant with a higher ABA content. Whilst jasmonic acid (JA) and JA-Ile concentrations increased in stressed leaves of the wild-type and the HvPap-1 knock-down lines, their levels were lower in the HvPap-19 knock-down lines, suggesting the involvement of a specific hormone interaction in the process. Our data indicate that the changes in leaf cuticle thickness and stomatal pore area had advantageous effects on leaf defense against fungal infection and mite feeding mediated by Magnaporthe oryzae and Tetranychus urticae, respectively., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)