cells Review Sarcoma Metabolomics: Current Horizons and Future Perspectives Miguel Esperança-Martins 1,2,3,* , Isabel Fernandes 1,3,4 , Joaquim Soares do Brito 4,5, Daniela Macedo 6, Hugo Vasques 4,7, Teresa Serafim 2, Luís Costa 1,3,4 and Sérgio Dias 2,4 1 Centro Hospitalar Universitário Lisboa Norte, Medical Oncology Department, Hospital Santa Maria, 1649-028 Lisboa, Portugal; [email protected] (I.F.); [email protected] (L.C.) 2 Vascular Biology & Cancer Microenvironment Lab, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; tserafi[email protected] (T.S.); [email protected] (S.D.) 3 Translational Oncobiology Lab, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal 4 Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; [email protected] (J.S.d.B.); [email protected] (H.V.) 5 Centro Hospitalar Universitário Lisboa Norte, Orthopedics and Traumatology Department, Hospital Santa Maria, 1649-028 Lisboa, Portugal 6 Medical Oncology Department, Hospital Lusíadas Lisboa, 1500-458 Lisboa, Portugal; [email protected] 7 General Surgery Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal * Correspondence: [email protected] Abstract: The vast array of metabolic adaptations that cancer cells are capable of assuming, not Citation: Esperança-Martins, M.; only support their biosynthetic activity, but also fulfill their bioenergetic demands and keep their Fernandes, I.; Soares do Brito, J.; intracellular reduction–oxidation (redox) balance. Spotlight has recently been placed on the en- Macedo, D.; Vasques, H.; Serafim, T.; ergy metabolism reprogramming strategies employed by cancer cells to proliferate. Knowledge Costa, L.; Dias, S. Sarcoma regarding soft tissue and bone sarcomas metabolome is relatively sparse. Further characterization of Metabolomics: Current Horizons and sarcoma metabolic landscape may pave the way for diagnostic refinement and new therapeutic target Future Perspectives. Cells 2021, 10, identification, with benefit to sarcoma patients. This review covers the state-of-the-art knowledge 1432. https://doi.org/10.3390/ on cancer metabolomics and explores in detail the most recent evidence on soft tissue and bone cells10061432 sarcoma metabolomics. Academic Editor: Gianpaolo Papaccio Keywords: sarcoma; soft tissue sarcoma; bone sarcoma; gastrointestinal stromal tumor; metabolomics; Received: 31 March 2021 metabolism Accepted: 4 June 2021 Published: 8 June 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in The knowledge regarding cancer cell properties has significantly evolved since the published maps and institutional affil- identification of the original hallmarks of cancer-sustaining proliferative signaling, evading iations. growth suppressors, activating invasion and metastases, enabling replicative immortal- ity, and inducing angiogenesis and resisting cell death [1]—and subsequent postulation of two additional ones—avoiding immune destruction and reprogramming of energy metabolism [2]. Copyright: © 2021 by the authors. Over recent decades, the spotlight has been placed on the metabolic adaptations Licensee MDPI, Basel, Switzerland. that cancer cells assume and in their proliferative capacity. Otto Warburg, a pioneer in This article is an open access article cancer metabolism research, observed that, even in oxygen-rich environments, cancer cells distributed under the terms and rearrange their glucose metabolism and restrain their energy metabolism to glycolysis [3]. conditions of the Creative Commons Recent developments have led to the comprehension of mechanisms by which specific Attribution (CC BY) license (https:// metabolic pathways are activated, enhanced, or reprogrammed, leading to the use of creativecommons.org/licenses/by/ accessible nutrients not only for production of metabolic precursors for cell anabolism and 4.0/). Cells 2021, 10, 1432. https://doi.org/10.3390/cells10061432 https://www.mdpi.com/journal/cells Cells 2021, 10, 1432 2 of 23 biosynthesis, but also to meet the bioenergetic demands required for cell perpetuation and for keeping an adequate intracellular reduction–oxidation (redox) balance [4]. This review covers the state-of-the-art knowledge on cancer metabolomics and ex- plores in detail the most recent evidence on soft tissue and bone sarcoma metabolomics, identifying potential biomarkers and therapeutic targets that may modulate these metabolic pathways. 2. Cancer Metabolic Fingerprints Neoplastic clones have the capability to adapt their metabolic activity to support the various tumorigenesis stages. These adaptations cover all phases of cell–metabolite interactions, influencing the metabolite inflow and increasing cell’s ability to obtain the necessary nutrients, shaping the way nutrients are selectively allocated to metabolic path- ways that fuel cellular tumorigenic adjustments, and providing long-ranging effects on cellular fate, amid which are changes in differentiation of both cancer cells and tumor microenvironment elements [5]. Metabolic reprogramming can be defined as the increase or suppression of standard metabolic pathways activity in cancer cells as a product of tu- morigenic mutations [6]. Oncometabolites are the metabolites whose quantity is markedly increased in cancer cells, with an existing link either between their accumulation and a particular mutation in the tumor, or between their presence and cancer development [6]. These rearrangements provide cancer cells with the power to fulfill their biosynthetic, bioenergetic and redox balance needs, and include three layers of cell-metabolite interac- tions (oncogene-directed nutrient uptake, intracellular metabolism reprogramming, and metabolite-directed changes in cell behavior/function). This metabolic reshaping may be summarized in six hallmarks of cancer metabolism: deregulated glucose and amino acid uptake, use of opportunistic modes of nutrient acquisition, use of glycolysis/tricarboxylic acid (TCA) cycle intermediates for biosynthesis and NADPH production, increased nitro- gen demand, alterations in metabolite-driven gene regulation, and metabolic interactions with the tumor microenvironment [5] (Figure1). 2.1. Deregulated Glucose and Amino Acid Uptake Cancer cells import or use different types of nutritional fuels to fulfill their core metabolic functions [7]. Glucose and glutamine are the two most prominent nutrients, and the main sources for maintenance of diverse carbon intermediates pools used as elementary units for assembly of diverse macromolecules, combustibles for adenosine triphosphate (ATP) generation, and cellular redox capacity enhancers [5]. Aerobic glycolysis (Warburg effect), the process of importing glucose and exporting carbon as lactate even in oxygen-rich environments, is the most widely explored metabolic pathway in cancer cells. When in cytosol, glucose may be used as a substrate in glycol- ysis (where the resulting pyruvate contributes to acetyl-CoA synthesis, crucial for the production of fatty acids, lipids and cholesterol, and non-essential amino acids aspartate and asparaginase [4]), in the hexosamine synthesis pathway (HSP), pentose phosphate pathway (PPP) [4], and serine biosynthesis pathway (SBP) [8]. Glucose catabolism is used by cancer cells as a way of generating precursors and intermediates for many other metabolic pathways. In benign cells, nutrient assimilation is regulated by growth factor signaling and cell interactions with the extracellular matrix [5]. Cancer cells carry a panoply of mu- tations that bestow them with a significant degree of independence from these external requirements [5]. Different mutations result in constitutive glucose uptake and metabolic adaptations [5]. Mutations in c-MYC, KRAS, and YAP oncogenes upregulate transmem- brane protein glucose transporter (GLUT) 1 expression, while overexpression of YAP and loss-of-function mutations in p53 augment GLUT3 expression, enhancing glucose entrance into the cell [8] (Figure1, Table1). In parallel, the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway is typically hyperactivated and acts as a master regulator of glucose uptake—by promoting GLUT1 mRNA expression and GLUT1 protein translocation from Cells 2021, 10, x FOR PEER REVIEW 2 of 25 biosynthesis, but also to meet the bioenergetic demands required for cell perpetuation and for keeping an adequate intracellular reduction–oxidation (redox) balance [4]. This review covers the state-of-the-art knowledge on cancer metabolomics and ex- plores in detail the most recent evidence on soft tissue and bone sarcoma metabolomics, identifying potential biomarkers and therapeutic targets that may modulate these meta- bolic pathways. 2. Cancer Metabolic Fingerprints Neoplastic clones have the capability to adapt their metabolic activity to support the various tumorigenesis stages. These adaptations cover all phases of cell–metabolite inter- actions, influencing the metabolite inflow and increasing cell’s ability to obtain the neces- sary nutrients, shaping the way nutrients are selectively allocated to metabolic pathways that fuel cellular tumorigenic adjustments, and providing long-ranging effects on cellular fate, amid which are changes in differentiation of both cancer cells and tumor microenvi- ronment elements [5]. Metabolic reprogramming can