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Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent activation of mTORC1 and glutamoptosis in vitro and in vivo. We also show that glutamine is used for asparagine synthesis and the GABA shunt to produce ATP and to inhibit AMPK, independently of glutaminolysis. Overall, our results indicate that glutamine metabolism is connected with mTORC1 activation through two parallel pathways: an acute alpha-ketoglutarate-dependent pathway; and a secondary ATP/AMPK-dependent pathway. This dual metabolic connection between glutamine and mTORC1 must be considered for the future design of therapeutic strategies to prevent cell growth in diseases such as cancer. ; This work was supported by funds from the following institutions: Agencia Estatal de Investigación/European Regional Development Fund, European Union (PGC2018-096244- B-I00, SAF2016-75442-R), Ministry of Science, Innovation and Universities of Spain, Spanish National Research Council—CSIC, Institut National de la Santé et de la Recherche Médicale —INSERM, Université de Bordeaux, Fondation pour la Recherche Médicale, the Conseil Régional d'Aquitaine, SIRIC-BRIO, Fondation ARC, and Institut Européen de Chimie et Biologie. C.B. was recipient of fellowships from the Minister of Higher Education, Research and Innovation (France) and the Fondation ARC (France).

Multi-omics datasets can provide molecular insights beyond the sum of individual omics. Various tools have been recently developed to integrate such datasets, but there are limited strategies to systematically extract mechanistic hypotheses from them. Here, we present COSMOS (Causal Oriented Search of Multi-Omics Space), a method that integrates phosphoproteomics, transcriptomics, and metabolomics datasets. COSMOS combines extensive prior knowledge of signaling, metabolic, and gene regulatory networks with computational methods to estimate activities of transcription factors and kinases as well as network-level causal reasoning. COSMOS provides mechanistic hypotheses for experimental observations across multi-omics datasets. We applied COSMOS to a dataset comprising transcriptomics, phosphoproteomics, and metabolomics data from healthy and cancerous tissue from eleven clear cell renal cell carcinoma (ccRCC) patients. COSMOS was able to capture relevant crosstalks within and between multiple omics layers, such as known ccRCC drug targets. We expect that our freely available method will be broadly useful to extract mechanistic insights from multi-omics studies. ; A.D. and E.G. were Marie-Curie Early Stage Researchers supported by the European Union's Horizon 2020 research and innovation program (675585 Marie-Curie ITN "SymBioSys") to J.S.R. A.D. was funded by German Federal Ministry of Education and Research (Bundesministerium fur Bildung und € Forschung BMBF) MSCoreSys research initiative research core SMART-CARE (031L0212A). This work was further supported by the JRC for Computational Biomedicine which was partially funded by Bayer AG, and the Medical Research Council (MC_UU_12022/6 to C.F. and M.S.). The Novo Nordisk Foundation Center for Protein Research is supported by Novo Nordisk Foundation grant number NNF14CC0001. J.V.O. was funded by a grant from Danish Council for Independent Research (8020-00100B) to partly support K.B.E. who was also supported in part by the Lundbeck Foundation (R193-2015-243). R.K. ...

Like normal hematopoietic stem cells, leukemic stem cells depend on their bone marrow (BM) microenvironment for survival, but the underlying mechanisms remain largely unknown. We have studied the contribution of nestin+ BM mesenchymal stem cells (BMSCs) to MLL-AF9-driven acute myeloid leukemia (AML) development and chemoresistance in vivo. Unlike bulk stroma, nestin+ BMSC numbers are not reduced in AML, but their function changes to support AML cells, at the expense of non-mutated hematopoietic stem cells (HSCs). Nestin+ cell depletion delays leukemogenesis in primary AML mice and selectively decreases AML, but not normal, cells in chimeric mice. Nestin+ BMSCs support survival and chemotherapy relapse of AML through increased oxidative phosphorylation, tricarboxylic acid (TCA) cycle activity, and glutathione (GSH)-mediated antioxidant defense. Therefore, AML cells co-opt energy sources and antioxidant defense mechanisms from BMSCs to survive chemotherapy. ; This work was supported by core support grants from the Well-come Trust (203151/Z/16/Z) and the MRC to the Cambridge Stem Cell Insti-tute, and the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia, Innovacion y Universidades (MCNU), and Pro CNIC Foundation to CNIC, which is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work was sup-ported by MCNU (Plan Nacional grant SAF-2011-30308 to S.M.-F.; Ramon y Cajal Program grants RYC-2011-09726 to A.S.-A. and RYC-2009-04703 toS.M.-F.); Marie Curie Career Integration Program grants (FP7-PEOPLE-2011-RG-294262/294096) to A.S.-A. and S.M.-F.; Spanish Ministry of Science, Innovation and Universities (BIO2015-67580-P and PGC2018-097019-B-I00), Carlos III Institute of Health-Fondo de Investigacio ́n Sanitaria grantPRB3 (IPT17/0019 - ISCIII-SGEFI/ ERDF, ProteoRed), Fundacio Marato TV3(grant 122/C/2015), and ''La Caixa'' Banking Foundation (project codeHR17-00247) to J.V.; the Medical Research Council grant MRC_MC_UU_12022/6 to C.F.; an ERC award (COMAL: 647685) and a CRUK Programme Award to B.J.H.; the Swiss National Science Foundation (SNF, 31003A_173224/1 & 31003A_149714) and the Gertrude von Meissner Foundation (Basel, Switzerland) to J.S.; ISCIII Spanish Cell Therapy Network TerCel, ConSEPOC-Comunidad de Madrid grant (S2010/BMD-2542), National Health Service Blood and Transplant (United Kingdom), European Union's Horizon 2020 research (ERC-2014-CoG-648765), and a Program Foundation Award (C61367/A26670) from Cancer Research UK to S.M.-F., who was also supported in part by an International Early Career Scientist grant of the Howard Hughes Medical Institute. ; Sí