Metabolic landscapes in sarcomas
Abstract
Metabolic rewiring offers novel therapeutic opportunities in cancer. Until recently, there was scant information regarding soft tissue sarcomas, due to their heterogeneous tissue origin, histological definition and underlying genetic history. Novel large-scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse metabolic landscapes condition the tumor microenvironment, anti-sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite-targeting drugs.
https://jhoonline.biomedcentral.com/art ... 21-01125-y
Metabolic landscapes in sarcomas
Re: Metabolic landscapes in sarcomas
Background
Sarcomas encompass a wide variety of tumors, with more than 170 subtypes, according to the last WHO classification. They originate from the neoplastic transformation of mesenchymal cells in connective tissues [1, 2]: 87% arise from soft tissue and 13% from bone [3, 4]. Soft tissue sarcoma (STS) presents as an indolent or aggressive disease, often only diagnosed at an advanced and/or metastatic stages. Current sarcoma classification relies on histopathology that may lead to errors in up to a quarter of cases [5]. In terms of prevalence, they represent less than 1% of adult cancers, but up to one fifth of pediatric solid malignant cancers [3]. Surgery is the standard of care for patients supplemented with chemotherapy or radiotherapy [6]. Targeted therapies remain limited to tumors with well-defined oncogenic drivers [1, 2]. Clinical trials targeting immune checkpoints show low response rates, with few responsive histotypes. Finally, biomarkers or tertiary lymphoid structures may be be predictive tools for 10% of patients [7]. Consequently, improving sarcoma typing and treatment requires the use of large-scale “omics” tools to identify the oncogenic drivers, often resulting from multiple genetic alterations in adult STS. These can include translocations, mutations or amplifications/deletions that cripple major growth and differentiation pathways [8,9,10,11,12].
Gene expression profiling of alveolar soft-part sarcoma (ASPS)
https://link.springer.com/article/10.11 ... -2407-9-22
Sarcomas encompass a wide variety of tumors, with more than 170 subtypes, according to the last WHO classification. They originate from the neoplastic transformation of mesenchymal cells in connective tissues [1, 2]: 87% arise from soft tissue and 13% from bone [3, 4]. Soft tissue sarcoma (STS) presents as an indolent or aggressive disease, often only diagnosed at an advanced and/or metastatic stages. Current sarcoma classification relies on histopathology that may lead to errors in up to a quarter of cases [5]. In terms of prevalence, they represent less than 1% of adult cancers, but up to one fifth of pediatric solid malignant cancers [3]. Surgery is the standard of care for patients supplemented with chemotherapy or radiotherapy [6]. Targeted therapies remain limited to tumors with well-defined oncogenic drivers [1, 2]. Clinical trials targeting immune checkpoints show low response rates, with few responsive histotypes. Finally, biomarkers or tertiary lymphoid structures may be be predictive tools for 10% of patients [7]. Consequently, improving sarcoma typing and treatment requires the use of large-scale “omics” tools to identify the oncogenic drivers, often resulting from multiple genetic alterations in adult STS. These can include translocations, mutations or amplifications/deletions that cripple major growth and differentiation pathways [8,9,10,11,12].
Gene expression profiling of alveolar soft-part sarcoma (ASPS)
https://link.springer.com/article/10.11 ... -2407-9-22
Last edited by D.ap on Sat Sep 11, 2021 7:34 am, edited 1 time in total.
Debbie
Re: Metabolic landscapes in sarcomas
Background cont..
Given the limits of current treatments, exploiting drugs targeting metabolic pathways may pave the way to effective therapy for these largely incurable diseases.
Aggressive tumors must survive in a reorganized, stressful and metabolically competitive microenvironment. This necessary adaptation exploits tumor heterogeneity and cell networks in the tumor microenvironment. Furthermore, within a given cell, plasticity depends on interconnections between various metabolic pathways to adapt growth to the available metabolites. A major trait often amplified in these tumors is the use of aerobic glycolysis, known as the Warburg effect [13], that optimizes tumor cell growth through provision of building blocks to increase biomass [14]. Since Warburg’s discovery, a debate has existed about the persistence of mitochondrial activity in glycolytic tumors and its potential to be a drug target [15]. Despite the central role of mitochondria not only in cell energetics, homeostasis and stress sensing [16] but also reactive oxygen species (ROS) production [17] their contribution to oncogenic transformation is still debated. In some STS, germline mutations affecting mitochondrial enzymes lead to the accumulation of oncometabolites that induce a pseudo-hypoxic response and alter epigenetic marks and differentiation [18]. In the tumor microenvironment, glycolytic and oxidizing cells may compete or cooperate for an optimal use and exchange of energetic metabolites. This network involves immune cells that adapt their metabolism to exert their functions in this competitive environment [19]. The purpose of this review is to link recent findings on STS genetics to the alterations of intracellular pathways affecting their tumor metabolic landscapes. Although not necessarily specific to STS, they may represent novel therapeutic opportunities.
Given the limits of current treatments, exploiting drugs targeting metabolic pathways may pave the way to effective therapy for these largely incurable diseases.
Aggressive tumors must survive in a reorganized, stressful and metabolically competitive microenvironment. This necessary adaptation exploits tumor heterogeneity and cell networks in the tumor microenvironment. Furthermore, within a given cell, plasticity depends on interconnections between various metabolic pathways to adapt growth to the available metabolites. A major trait often amplified in these tumors is the use of aerobic glycolysis, known as the Warburg effect [13], that optimizes tumor cell growth through provision of building blocks to increase biomass [14]. Since Warburg’s discovery, a debate has existed about the persistence of mitochondrial activity in glycolytic tumors and its potential to be a drug target [15]. Despite the central role of mitochondria not only in cell energetics, homeostasis and stress sensing [16] but also reactive oxygen species (ROS) production [17] their contribution to oncogenic transformation is still debated. In some STS, germline mutations affecting mitochondrial enzymes lead to the accumulation of oncometabolites that induce a pseudo-hypoxic response and alter epigenetic marks and differentiation [18]. In the tumor microenvironment, glycolytic and oxidizing cells may compete or cooperate for an optimal use and exchange of energetic metabolites. This network involves immune cells that adapt their metabolism to exert their functions in this competitive environment [19]. The purpose of this review is to link recent findings on STS genetics to the alterations of intracellular pathways affecting their tumor metabolic landscapes. Although not necessarily specific to STS, they may represent novel therapeutic opportunities.
Debbie
Re: Metabolic landscapes in sarcomas
Unsupervised omics and single cell-based analyses highlight metabolic signatures in cancer
Exploration of the TCGA database allows one to identify more discrete signatures displayed by major STS subtypes versus other types of cancers. As shown in Fig. 1, all cancer types display abnormalities in cell cycle regulation. Most carcinomas show an enrichment in oncogenic pathways, glycolytic signatures and alterations of energetic, nucleotide, amino acid or macromolecule pathways. When considering STS as a whole, RAS, PI3K and HIPPO pathways light up, as in [8], coupled to a dominant glycolytic/OXPHOS signature. More discrete signals confirm the enhancement of the PGI pathway in STS, although this trend is not detectable when considering individually the STS subtypes. Our analysis also indicates that distinct signatures preferentially match with STS subtypes, with UPS featuring an enrichment in PPAR/fatty acids and glycine/serine/threonine pathways, whereas LMS display an enhanced OXPHOS signature. Similarly, differences in oncogenic pathway usage are apparent but it is difficult to relate these pathways to the metabolic bias in tumors.
The development of more integrated technologies with increased sensitivity and/or resolution has helped to unravel tumor genomic and metabolic complexity in situ and to bridge the gap between mouse models and patients. Several recent studies documented the power of integrated genomic or metabolomic strategies to decipher tumors complexity. An article from The Cancer Genome Atlas (TCGA) Research Network [8] combined genetic, epigenetic and transcriptomic analyses and proposed a novel classification of STS subtypes with complex genomes. In their analysis of the number and nature of copy number variations (CNVs), they identified three dominant profiles from leiomyosarcoma (LMS), myxofibrosarcoma (MFS), undifferentiated pleomorphic sarcoma (UPS) to dedifferentiated liposarcoma (DDLPS) displaying the highest level of genomic alterations. In addition to these modifications, the nature of epigenetics marks, activating pathways or immune signatures add further prognostic value. Another article exploited TCGA data to describe the relative contribution of 114 metabolic pathways to cancer progression [20]. This analysis showed that master metabolic transcriptional regulators behave as genetic drivers explaining the metabolic profiles displayed by various tumors compared to normal tissues, and help predict responsiveness to metabolism-targeting drugs. For example, alterations of specific transcriptional regulators explain the defect in polyamine biosynthesis in prostate cancer. Similarly, distinct pathways enriched in breast cancer allow the discrimination of aggressive tumors from those associated with a good prognostic. Based on this finding, metformin, a mitochondrial complex 1 inhibitor, has been proposed as a potential adjunct therapy against basal breast cancer cells, due to its unique deregulation of the Tricarboxylic Acid (TCA) cycle. In STS, this analysis highlighted the enrichment in the pentose and glucuronate interconversion (PGI) pathway, also amplified in the Yang Huang syndrome described in the context of traditional Chinese pharmacology [21]. The PGI pathway relies on UDP-glucuronosyltransferase (UGT) enzymes that catalyze the binding of D-glucuronic acid to toxic substances or endogenous compounds such as bilirubin via glycosidic bonds, contributing to the detoxification of lipophilic compounds or glucuronides.The word omics refers to a field of study in biological sciences that ends with -omics, such as genomics, transcriptomics, proteomics, or metabolomics. The ending -ome is used to address the objects of study of such fields, such as the genome, proteome, transcriptome, or metabolome, respectively.Aug 11, 2017
Exploration of the TCGA database allows one to identify more discrete signatures displayed by major STS subtypes versus other types of cancers. As shown in Fig. 1, all cancer types display abnormalities in cell cycle regulation. Most carcinomas show an enrichment in oncogenic pathways, glycolytic signatures and alterations of energetic, nucleotide, amino acid or macromolecule pathways. When considering STS as a whole, RAS, PI3K and HIPPO pathways light up, as in [8], coupled to a dominant glycolytic/OXPHOS signature. More discrete signals confirm the enhancement of the PGI pathway in STS, although this trend is not detectable when considering individually the STS subtypes. Our analysis also indicates that distinct signatures preferentially match with STS subtypes, with UPS featuring an enrichment in PPAR/fatty acids and glycine/serine/threonine pathways, whereas LMS display an enhanced OXPHOS signature. Similarly, differences in oncogenic pathway usage are apparent but it is difficult to relate these pathways to the metabolic bias in tumors.
Debbie
Re: Metabolic landscapes in sarcomas
The PGI pathway relies on UDP-glucuronosyltransferase (UGT) enzymes that catalyze the binding of D-glucuronic acid to toxic substances or endogenous compounds such as bilirubin via glycosidic bonds, contributing to the detoxification of lipophilic compounds or glucuronides.
Debbie