Cysteine as a Carbon Source, a Hot Spot in Cancer Cells Survival

Cancer cells undergo a metabolic rewiring in order to fulfill the energy and biomass requirements. Cysteine is a pivotal organic compound that contributes for cancer metabolic remodeling at three different levels: (1) in redox control, free or as a component of glutathione; (2) in ATP production, via hydrogen sulfide (H2S) production, serving as a donor to electron transport chain (ETC), and (3) as a carbon source for biomass and energy production. In the present review, emphasis will be given to the role of cysteine as a carbon source, focusing on the metabolic reliance on cysteine, benefiting the metabolic fitness and survival of cancer cells. Therefore, the interplay between cysteine metabolism and other metabolic pathways, as well as the regulation of cysteine metabolism related enzymes and transporters, will be also addressed. Finally, the usefulness of cysteine metabolic route as a target in cancer treatment will be highlighted.publishersversionpublishe

An integrative view on glucagon function and putative role in the progression of pancreatic neuroendocrine tumours (pNETs) and hepatocellular carcinomas (HCC)

Funding Information: The institutions are funded by Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior (FCT/MCTES, Portugal) through national funds to iNOVA4Health ( UIDB/04462/2020 and UIDP/04462/2020 ) and the Associated Laboratory LS4FUTURE ( LA/P/0087/2020 ). Funding Information: Lipids metabolism is relevant to sustain pNETs and HCC. Little is known on lipids metabolism in pNETs cancer models, but in pNETs patients, a poor prognosis association was observed with increased levels of expression of acetyl-Co carboxylase 1 (ACC1) and FA synthase (FASN), moreover this study supported that systemic and tumour increased lipid bioavailability are associated with decreased progression-free survival (PFS) of advanced pNETs patients treated with everolimus, a mTOR inhibitor (Vernieri et al., 2019a). The inhibition of mTOR is an important therapeutical approach since abnormal PI3K-Akt/PKB-mTOR pathway signalling has been implicated in the pathogenesis of pNETs (Goldstein and Meyer, 2011). Interestingly, everomilus present as side effects hyperglycaemia, hyperglyceridaemia and hypercholesterolaemia (Vernieri et al., 2019b), indicating that PI3K pathway interferes with metabolism and is a core controller of pNETs’ metabolic remodelling, in which glucagon may be a key activator. In HCC, the upregulation of FAs anabolism and catabolism, as well as the increased uptake is described as crucial in tumorigenesis and disease progression, as reviewed (Sangineto et al., 2020b). The FA metabolic usage is dependent on the TOME and the genetic profile of tumours, varying according to the clinical context of HCC. Upon oxygen and nutrients scarcity, β-catenin-activated HCC cells increase the uptake of FA from the TOME together with the β-oxidation rate (Iwamoto et al., 2018). Although β-oxidation suppression favoured HCC development in obesity and non-alcoholic steatohepatitis (NASH) contexts (Sangineto et al., 2020c). FA de novo synthesis also has a role in tumoral progression, since ACC1 enzyme has been associated with HCC cell survival under glucose scarcity (Wang et al., 2016c). Furthermore, the fundamental role of FASN in HCC has been demonstrated by genetic silencing and enzyme inhibition, in studies dedicated to HCC in vitro and in vivo models (Calvisi et al., 2011; HAO et al., 2014; Li et al., 2016).The institutions are funded by Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior (FCT/MCTES, Portugal) through national funds to iNOVA4Health (UIDB/04462/2020 and UIDP/04462/2020) and the Associated Laboratory LS4FUTURE (LA/P/0087/2020). Publisher Copyright: © 2023 The AuthorsCancer metabolism research area evolved greatly, however, is still unknown the impact of systemic metabolism control and diet on cancer. It makes sense that systemic regulators of metabolism can act directly on cancer cells and activate signalling, prompting metabolic remodelling needed to sustain cancer cell survival, tumour growth and disease progression. In the present review, we describe the main glucagon functions in the control of glycaemia and of metabolic pathways overall. Furthermore, an integrative view on how glucagon and related signalling pathways can contribute for pancreatic neuroendocrine tumours (pNETs) and hepatocellular carcinomas (HCC) progression, since pancreas and liver are the major organs exposed to higher levels of glucagon, pancreas as a producer and liver as a scavenger. The main objective is to bring to discussion some glucagon-dependent mechanisms by presenting an integrative view on microenvironmental and systemic aspects in pNETs and HCC biology.publishersversionpublishe

An Accomplice for New Therapeutic Strategies to Fight Lung Cancer

The research was funded by iNOVA4Health—UID/Multi/04462, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência (FCT-MCTES), through national funds and co-funded by FEDER under the PT2020 Partnership Agreement.Metabolic remodelling is a hallmark of cancer, however little has been unravelled in its role in chemoresistance, which is a major hurdle to cancer control. Lung cancer is a leading cause of death by cancer, mainly due to the diagnosis at an advanced stage and to the development of resistance to therapy. Targeted therapeutic agents combined with comprehensive drugs are commonly used to treat lung cancer. However, resistance mechanisms are difficult to avoid. In this review, we will address some of those therapeutic regimens, resistance mechanisms that are eventually developed by lung cancer cells, metabolic alterations that have already been described in lung cancer and putative new therapeutic strategies, and the integration of conventional drugs and genetic and metabolic-targeted therapies. The oxidative stress is pivotal in this whole network. A better understanding of cancer cell metabolism and molecular adaptations underlying resistance mechanisms will provide clues to design new therapeutic strategies, including the combination of chemotherapeutic and targeted agents, considering metabolic intervenients. As cancer cells undergo a constant metabolic adaptive drift, therapeutic regimens must constantly adapt.publishersversionpublishe

Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression

The way cancer cells adapt to microenvironment is crucial for the success of carcinogenesis, and metabolic fitness is essential for a cancer cell to survive and proliferate in a certain organ/tissue. The metabolic remodeling in a tumor niche is endured not only by cancer cells but also by non-cancerous cells that share the same microenvironment. For this reason, tumor cells and stromal cells constitute a complex network of signal and organic compound transfer that supports cellular viability and proliferation. The intensive dual-address cooperation of all components of a tumor sustains disease progression and metastasis. Herein, we will detail the role of cancer-associated fibroblasts, cancer-associated adipocytes, and inflammatory cells, mainly monocytes/macrophages (tumor-associated macrophages), in the remodeling and metabolic adaptation of tumors.publishersversionpublishe

Take advantage of glutamine anaplerosis, the kernel of the metabolic rewiring in malignant gliomas

Glutamine is a non-essential amino acid that plays a key role in the metabolism of proliferating cells including neoplastic cells. In the central nervous system (CNS), glutamine metabolism is particularly relevant, because the glutamine-glutamate cycle is a way of controlling the production of glutamate-derived neurotransmitters by tightly regulating the bioavailability of the amino acids in a neuron-astrocyte metabolic symbiosis-dependent manner. Glutamine-related metabolic adjustments have been reported in several CNS malignancies including malignant gliomas that are considered ‘glutamine addicted’. In these tumors, glutamine becomes an essential amino acid preferentially used in energy and biomass production including glutathione (GSH) generation, which is crucial in oxidative stress control. Therefore, in this review, we will highlight the metabolic remodeling that gliomas undergo, focusing on glutamine metabolism. We will address some therapeutic regimens including novel research attempts to target glutamine metabolism and a brief update of diagnosis strategies that take advantage of this altered profile. A better understanding of malignant glioma cell metabolism will help in the identification of new molecular targets and the design of new therapies.publishersversionpublishe

A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer

Metabolic remodeling is a critical skill of malignant cells, allowing their survival and spread. The metabolic dynamics and adaptation capacity of cancer cells allow them to escape from damaging stimuli, including breakage or cross-links in DNA strands and increased reactive oxygen species (ROS) levels, promoting resistance to currently available therapies, such as alkylating or oxidative agents. Therefore, it is essential to understand how metabolic pathways and the corresponding enzymatic systems can impact on tumor behavior. Cysteine aminotransferase (CAT) per se, as well as a component of the CAT: 3-mercaptopyruvate sulfurtransferase (MST) axis, is pivotal for this metabolic rewiring, constituting a central mechanism in amino acid metabolism and fulfilling the metabolic needs of cancer cells, thereby supplying other different pathways. In this review, we explore the current state-of-art on CAT function and its role on cancer cell metabolic rewiring as MST partner, and its relevance in cancer cells' fitness.publishersversionpublishe

Current challenges and future perspectives

: The research group was funded by IPOLFG EPE and by iNOVA4Health (UID/Multi/04462/2019) a program financially supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Educação e Ciência, through national funds. We also acknowledge funding from FCT-MCTES through Filipa Lopes-Coelho PhD (PD/BD/128337/2017).Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.publishersversionpublishe

Metabolic Profiles Point Out Metabolic Pathways Pivotal in Two Glioblastoma (GBM) Cell Lines, U251 and U-87MG

Funding Information: The institutions are funded by Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior (FCT/MCTES, Portugal) through national funds to iNOVA4Health (UIDB/04462/2020 and UIDP/04462/2020), to MOSTMICRO-ITQB (UIDB/04612/2020 and UIDP/04612/2020), and the Associated Laboratory LS4FUTURE (LA/P/0087/2020). Filipa Martins was funded by an FCT individual Ph.D. fellowship (2020.04780.BD). Luis G. Gonçalves was financed by a FCT contract according to DL57/2016, (SFRH/BPD/111100/2015). This work benefited from access to CERMAX, ITQB-NOVA, Oeiras, Portugal with equipment funded by FCT, project AAC 01/SAICT/2016. Publisher Copyright: © 2023 by the authors.Glioblastoma (GBM) is the most lethal central nervous system (CNS) tumor, mainly due to its high heterogeneity, invasiveness, and proliferation rate. These tumors remain a therapeutic challenge, and there are still some gaps in the GBM biology literature. Despite the significant amount of knowledge produced by research on cancer metabolism, its implementation in cancer treatment has been limited. In this study, we explored transcriptomics data from the TCGA database to provide new insights for future definition of metabolism-related patterns useful for clinical applications. Moreover, we investigated the impact of key metabolites (glucose, lactate, glutamine, and glutamate) in the gene expression and metabolic profile of two GBM cell lines, U251 and U-87MG, together with the impact of these organic compounds on malignancy cell features. GBM cell lines were able to adapt to the exposure to each tested organic compound. Both cell lines fulfilled glycolysis in the presence of glucose and were able to produce and consume lactate. Glutamine dependency was also highlighted, and glutamine and glutamate availability favored biosynthesis observed by the increase in the expression of genes involved in fatty acid (FA) synthesis. These findings are relevant and point out metabolic pathways to be targeted in GBM and also reinforce that patients’ metabolic profiling can be useful in terms of personalized medicine.publishersversionpublishe

Pulling the Strings Toward Tumor Metastasis

Funding: The research group was funded by IPOLFG EPE and by iNOVA4Health (UID/Multi/04462/2019) a program financially supported by Fundação para a Ciência e Tecnologia (FCT)/ Ministério da Educação e Ciência, through national funds. All the fellowships were funded by FCT: AH (SFRH/BD/148441/ 2019), FM (2020.04780.BD), CM (2020.06956.BD), FL-C (PD/ BD/128337/2017).Metastasis is a major hurdle to the efficient treatment of cancer, accounting for the great majority of cancer-related deaths. Although several studies have disclosed the detailed mechanisms underlying primary tumor formation, the emergence of metastatic disease remains poorly understood. This multistep process encompasses the dissemination of cancer cells to distant organs, followed by their adaptation to foreign microenvironments and establishment in secondary tumors. During the last decades, it was discovered that these events may be favored by particular metabolic patterns, which are dependent on reprogrammed signaling pathways in cancer cells while they acquire metastatic traits. In this review, we present current knowledge of molecular mechanisms that coordinate the crosstalk between metastatic signaling and cellular metabolism. The recent findings involving the contribution of crucial metabolic pathways involved in the bioenergetics and biosynthesis control in metastatic cells are summarized. Finally, we highlight new promising metabolism-based therapeutic strategies as a putative way of impairing metastasis.publishersversionpublishe