bims-glucam 2022-11-06 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–11–06
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Tumor glycolysis, an essential sweet tooth of tumor cells.
Genome-Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer Treatment.
Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
Glial Glutamine Homeostasis in Health and Disease.
Coupling-dependent metabolic ultradian rhythms in confluent cells.
Glutamine metabolism in cancers: Targeting the oxidative homeostasis.
Metabolic features of myeloma cells in the context of bone microenvironment: Implication for the pathophysiology and clinic of myeloma bone disease.
Transient Systemic Autophagy Ablation Irreversibly Inhibits Lung Tumor Cell Metabolism and Promotes T-Cell Mediated Tumor Killing.
Understanding the molecular mechanisms of macrophage polarization and metabolic reprogramming in endometriosis: A narrative review.
Glutamine increases stability of TPH1 mRNA via p38 mitogen-activated kinase in mouse mastocytoma cells.
A functional analysis of 180 cancer cell lines reveals conserved intrinsic metabolic programs.
AKT supports the metabolic fitness of multiple myeloma cells by restricting FOXO activity.
Metabolism and Colorectal Cancer.
Heterogeneity of the cancer cell line metabolic landscape.
A novel amino acid metabolism-related gene risk signature for predicting prognosis in clear cell renal cell carcinoma.
Plasticity of cancer invasion and energy metabolism.

Semin Cancer Biol. 2022 Oct 28. pii: S1044-579X(22)00204-8. [Epub ahead of print]86(Pt 3): 1216-1230

Tumor glycolysis, an essential sweet tooth of tumor cells.

Sumana Paul, Saikat Ghosh, Sushil Kumar.

  Cancer cells undergo metabolic alterations to meet the immense demand for energy, building blocks, and redox potential. Tumors show glucose-avid and lactate-secreting behavior even in the presence of oxygen, a process known as aerobic glycolysis. Glycolysis is the backbone of cancer cell metabolism, and cancer cells have evolved various mechanisms to enhance it. Glucose metabolism is intertwined with other metabolic pathways, making cancer metabolism diverse and heterogeneous, where glycolysis plays a central role. Oncogenic signaling accelerates the metabolic activities of glycolytic enzymes, mainly by enhancing their expression or by post-translational modifications. Aerobic glycolysis ferments glucose into lactate which supports tumor growth and metastasis by various mechanisms. Herein, we focused on tumor glycolysis, especially its interactions with the pentose phosphate pathway, glutamine metabolism, one-carbon metabolism, and mitochondrial oxidation. Further, we describe the role and regulation of key glycolytic enzymes in cancer. We summarize the role of lactate, an end product of glycolysis, in tumor growth, and the metabolic adaptations during metastasis. Lastly, we briefly discuss limitations and future directions to improve our understanding of glucose metabolism in cancer.

Keywords:  Cancer metabolism; Lactate; Metastasis; Tumor glycolysis; metabolic adaptations

DOI:  https://doi.org/10.1016/j.semcancer.2022.09.007
Adv Sci (Weinh). 2022 Oct 30. e2202104

Genome-Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer Treatment.

Chunxue Yang, Derek Lee, Misty Shuo Zhang, Aki Pui-Wah Tse, Lai Wei, Macus Hao-Ran Bao, Bowie Po-Yee Wong, Cerise Yuen-Ki Chan, Vincent Wai-Hin Yuen, Yiling Chen, Carmen Chak-Lui Wong.

  Hepatocellular carcinoma (HCC) is the second most lethal cancer worldwide. Glutamine is an essential, extracellular nutrient which supports HCC growth. Dietary glutamine deficiency may be a potential therapeutic approach for HCC. HCC cells overcome metabolic challenges by rewiring their metabolic pathways for rapid adaptations. The efficiency of dietary glutamine deficiency as HCC treatment is examined and the adaptation machinery under glutamine depletion in HCC cells is unraveled. Using genome-wide CRISPR/Cas9 knockout library screening, this study identifies that pyruvate dehydrogenase α (PDHA), pyruvate dehydrogenase β (PDHB), and pyruvate carboxylase (PC) in pyruvate metabolism are crucial to the adaptation of glutamine depletion in HCC cells. Knockout of either PDHA, PDHB or PC induced metabolic reprogramming of the tricarboxylic acid (TCA) cycle, disrupts mitochondrial function, leading to the suppression of HCC cell proliferation under glutamine depletion. Surprisingly, dietary glutamine restriction improves therapeutic responses of HCC to PDH or PC inhibitor in mouse HCC models. Stable isotope carbon tracing confirms that PDH or PC inhibitors further disrupt the metabolic rewiring of the TCA cycle induced by dietary glutamine depletion in HCC. In summary, the results demonstrate that pyruvate metabolism acts as novel targetable metabolic vulnerabilities for HCC treatment in combination with a glutamine-deficient diet.

Keywords:  CRISPR/Cas9 library screening; dietary intervention; glutamine depletion; hepatocellular carcinoma; pyruvate metabolism

DOI:  https://doi.org/10.1002/advs.202202104
Mol Cell. 2022 Oct 31. pii: S1097-2765(22)00962-5. [Epub ahead of print]

Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.

Patricia Altea-Manzano, Anke Vandekeere, Joy Edwards-Hicks, Mar Roldan, Emily Abraham, Xhordi Lleshi, Ania Naila Guerrieri, Domenica Berardi, Jimi Wills, Jair Marques Junior, Asimina Pantazi, Juan Carlos Acosta, Rosario M Sanchez-Martin, Sarah-Maria Fendt, Miguel Martin-Hernandez, Andrew J Finch.

  Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.

Keywords:  anaplerosis; cancer; cancer metabolism; metabolism; mitochondrion; redox; redox transfer; respiration

DOI:  https://doi.org/10.1016/j.molcel.2022.10.005
Neurochem Res. 2022 Nov 02.

Glial Glutamine Homeostasis in Health and Disease.

Jens V Andersen, Arne Schousboe.

  Glutamine is an essential cerebral metabolite. Several critical brain processes are directly linked to glutamine, including ammonia homeostasis, energy metabolism and neurotransmitter recycling. Astrocytes synthesize and release large quantities of glutamine, which is taken up by neurons to replenish the glutamate and GABA neurotransmitter pools. Astrocyte glutamine hereby sustains the glutamate/GABA-glutamine cycle, synaptic transmission and general brain function. Cerebral glutamine homeostasis is linked to the metabolic coupling of neurons and astrocytes, and relies on multiple cellular processes, including TCA cycle function, synaptic transmission and neurotransmitter uptake. Dysregulations of processes related to glutamine homeostasis are associated with several neurological diseases and may mediate excitotoxicity and neurodegeneration. In particular, diminished astrocyte glutamine synthesis is a common neuropathological component, depriving neurons of an essential metabolic substrate and precursor for neurotransmitter synthesis, hereby leading to synaptic dysfunction. While astrocyte glutamine synthesis is quantitatively dominant in the brain, oligodendrocyte-derived glutamine may serve important functions in white matter structures. In this review, the crucial roles of glial glutamine homeostasis in the healthy and diseased brain are discussed. First, we provide an overview of cellular recycling, transport, synthesis and metabolism of glutamine in the brain. These cellular aspects are subsequently discussed in relation to pathological glutamine homeostasis of hepatic encephalopathy, epilepsy, Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis. Further studies on the multifaceted roles of cerebral glutamine will not only increase our understanding of the metabolic collaboration between brain cells, but may also aid to reveal much needed therapeutic targets of several neurological pathologies.

Keywords:  Astrocytes; Brain energy and neurotransmitter metabolism; GABA-glutamine cycle; Glutamate-glutamine cycle; Glutamine transporters; Neurodegenerative diseases; Oligodendrocytes

DOI:  https://doi.org/10.1007/s11064-022-03771-1
Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2211142119

Coupling-dependent metabolic ultradian rhythms in confluent cells.

Shuzhang Yang, Shin Yamazaki, Kimberly H Cox, Yi-Lin Huang, Evan W Miller, Joseph S Takahashi.

  Ultradian rhythms in metabolism and physiology have been described previously in mammals. However, the underlying mechanisms for these rhythms are still elusive. Here, we report the discovery of temperature-sensitive ultradian rhythms in mammalian fibroblasts that are independent of both the cell cycle and the circadian clock. The period in each culture is stable over time but varies in different cultures (ranging from 3 to 24 h). We show that transient, single-cell metabolic pulses are synchronized into stable ultradian rhythms across contacting cells in culture by gap junction-mediated coupling. Coordinated rhythms are also apparent for other metabolic and physiological measures, including plasma membrane potential (Δψp), intracellular glutamine, α-ketoglutarate, intracellular adenosine triphosphate (ATP), cytosolic pH, and intracellular calcium. Moreover, these ultradian rhythms require extracellular glutamine, several different ion channels, and the suppression of mitochondrial ATP synthase by α-ketoglutarate, which provides a key feedback mechanism. We hypothesize that cellular coupling and metabolic feedback can be used by cells to balance energy demands for survival.

Keywords:  cellular metabolism; gap junctions; ion channels; membrane potential; ultradian rhythms

DOI:  https://doi.org/10.1073/pnas.2211142119
Front Oncol. 2022 ;12 994672

Glutamine metabolism in cancers: Targeting the oxidative homeostasis.

Tengfang Gong, Changbing Zheng, Xidan Ou, Jie Zheng, Jiayi Yu, Shuyu Chen, Yehui Duan, Wei Liu.

  Glutamine is the most abundant amino acid in blood and tissues, and the most important nutrient except for glucose in cancer cells. Over the past years, most studies have focused on the role of Gln metabolism in supporting energy metabolism rather than maintaining oxidative homeostasis. In fact, Gln is an important factor in maintaining oxidative homeostasis of cancer cells, especially in "Glutamine addicted" cancer cells. Here, this paper will review the recent scientific literature about the link between Gln metabolism and oxidative homeostasis, with an emphasis on the potential role of Gln metabolism in different cancers. Given that oxidative homeostasis is of critical importance in cancer, understanding the impacts of a Gln metabolism on oxidative homeostasis, gaining great insights into underlying molecular mechanisms, and developing effective therapeutic strategies are of great importance.

Keywords:  Gln metabolism; ROS; cancer cells; health; oxidative homeostasis

DOI:  https://doi.org/10.3389/fonc.2022.994672
Front Oncol. 2022 ;12 1015402

Metabolic features of myeloma cells in the context of bone microenvironment: Implication for the pathophysiology and clinic of myeloma bone disease.

Vincenzo Raimondi, Denise Toscani, Valentina Marchica, Jessica Burroughs-Garcia, Paola Storti, Nicola Giuliani.

  Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of malignant plasma cells (PCs) into the bone marrow (BM). The complex interaction between the BM microenvironment and MM PCs can lead to severe impairment of bone remodeling. Indeed, the BM microenvironment exerts a critical role in the survival of malignant PCs. Growing evidence indicates that MM cells have several metabolic features including enhanced glycolysis and an increase in lactate production through the upregulation of glucose transporters and enzymes. More recently, it has been reported that MM cells arehighly glutamine addicted. Interestingly, these metabolic changes in MM cells may affect BM microenvironment cells by altering the differentiation process of osteoblasts from mesenchymal stromal cells. The identification of glutamine metabolism alterations in MM cells and bone microenvironment may provide a rationale to design new therapeutic approaches and diagnostic tools. The osteolytic lesions are the most frequent clinical features in MM patients, often characterized by pathological fractures and acute pain. The use of the newer imaging techniques such as Magnetic Resonance Imaging (MRI) and combined Positron Emission Tomography (PET) and Computerized Tomography (CT) has been introduced into clinical practice to better define the skeletal involvement. Currently, the PET/CT with 18F-fluorodeoxyglucose (FDG) is the diagnostic gold standard to detect active MM bone disease due to the high glycolytic activity of MM cells. However, new tracers are actively under investigation because a portion of MM patients remains negative at the skeletal level by 18F-FDG. In this review, we will summarize the existing knowledge on the metabolic alterations of MM cells considering their impact on the BM microenvironment cells and particularly in the subsequent formation of osteolytic bone lesions. Based on this, we will discuss the identification of possible new druggable targets and the use of novel metabolic targets for PET imaging in the detection of skeletal lesions, in the staging and treatment response of MM patients.

Keywords:  glutamine; imaging; metabolism; myeloma; osteoblast; osteoclast

DOI:  https://doi.org/10.3389/fonc.2022.1015402
Autophagy. 2022 Oct 31.

Transient Systemic Autophagy Ablation Irreversibly Inhibits Lung Tumor Cell Metabolism and Promotes T-Cell Mediated Tumor Killing.

Kyle Nunn, Jessie Yanxiang Guo.

  Macroautophagy/autophagy is a highly conserved catabolic process pivotal to cellular homeostasis and support of tumorigenesis. Being a potential therapeutic target for cancer, we have worked to understand the implications of autophagy inhibition both systemically, and tumor-specifically. We utilized inducible expression of Atg5 shRNA to temporally control autophagy levels in a reversible manner to study the effects of tumor-intrinsic and systemic autophagic loss and restoration on established KrasG12D/+;trp53-/- (KP) lung tumor growth. We reported that transient systemic ATG5 loss significantly reduces KP lung tumor growth. Through in vivo isotope tracing and metabolic flux analyses, we noted that systemic ATG5 knockdown significantly reduces the uptake of glucose and lactate in lung tumors, leading to impaired TCA cycle metabolism and biosynthesis. Additionally, we observed an increased tumor T cell infiltration in the absence of systemic ATG5, which is essential for T cell-mediated tumor killing. Moreover, the impaired tumor metabolism and increased T cell infiltration are sustained when autophagy is restored in a short term. Finally, we found that intermittent systemic ATG5 knockdown, a mock therapy situation, significantly prolongs the lifespan of mice bearing KP lung tumors. Our findings lay the proof of concept for inhibition of autophagy as a valid approach to cancer therapy.

Keywords:  KRAS; autophagy; cancer metabolism; cancer therapy; immune evasion; lung tumor

DOI:  https://doi.org/10.1080/15548627.2022.2141534
Reprod Med Biol. 2022 Jan-Dec;21(1):21(1): e12488

Understanding the molecular mechanisms of macrophage polarization and metabolic reprogramming in endometriosis: A narrative review.

Hiroshi Kobayashi, Shogo Imanaka.

   Background: Endometriosis is an estrogen-dependent disease and causes pelvic pain and infertility. The limits of current pharmacotherapy in women who desire to become pregnant prompt the development of various targeted molecules for more effective treatment. A review article focused on the unique aspect of cellular metabolic reprogramming of endometriotic cells has been reported. The cellular metabolic pathways are reprogrammed to adapt to a variety of environmental stresses (e.g., nutrient starvation or glucose deprivation, hypoxic stress, excessive reactive oxygen species generation, and other environmental factors). This review aims to summarize macrophage polarization and metabolic reprogramming in endometriosis.
Methods: A literature search was performed between January 2000 and March 2022 in the PubMed and Google Scholar databases using a combination of specific terms.
Results: Macrophage cellular metabolism has a marked influence on its phenotype and function. Preclinical studies showed that metabolic conversion toward glycolysis or oxidative phosphorylation drives macrophage polarization to M1 or M2 phenotype, respectively. Such cellular metabolic rewiring can offer new therapeutic opportunities.
Conclusion: A better understanding of metabolic reprogramming biology in endometriosis-associated macrophages is essential in considering novel therapeutic approach for endometriosis. However, there are currently no detailed studies on therapeutic strategies targeting the cellular metabolic properties of endometriosis-associated macrophages.

Keywords:  endometriosis; macrophages; metabolic reprogramming; phenotype

DOI:  https://doi.org/10.1002/rmb2.12488
Mol Biol Rep. 2022 Nov 04.

Glutamine increases stability of TPH1 mRNA via p38 mitogen-activated kinase in mouse mastocytoma cells.

Heeyoung Park, Chang-Wook Lee, Jieun Kang, Ali Sadra, Sung-Oh Huh.

  Expression changes for tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in serotonin synthesis, by environmental glutamine (GLN) were examined in mouse mastocytoma-derived P815-HTR cells. GLN-treated cells exhibited a robust increase in TPH1 mRNA after a 6 h exposure to GLN. 6-Diazo-5-oxo-L-norleucine (DON), a glutamine-utilizing glutaminase inhibitor, significantly inhibited the GLN-induction of TPH1 mRNA. Nuclear run-on assays and mRNA decay experiments demonstrated that the primary mechanism leading to increased TPH1 mRNA levels was not due to transcriptional changes, but rather due to increased TPH1 RNA stability induced by GLN. Treatment with GLN also led to activation of p38 MAP kinase, but not p42/44 MAPK. In addition, SB203580, a p38 MAP kinase specific inhibitor, completely abolished the GLN-mediated increase of TPH1 mRNA levels, suggesting the pathway stabilizing TPH1 mRNA might be mediated by the activated p38 MAP kinase pathway. Additionally, SB203580 significantly reduced the stability of TPH1 mRNA, and this reduction of the stability was not affected by GLN in the culture medium, implying a sequential signaling from GLN being mediated by p38 MAP kinase, resulting in alteration of TPH1 mRNA stability. TPH1 mRNA stability loss was also dependent on de novo protein synthesis as shown by treatment of cells with a transcriptional/translational blocker. We provide evidence that TPH1 mRNA levels are increased in response to increased exogenous GLN in mouse mastocytoma cells via a stabilization of TPH1 mRNA due to the activity of the p38 MAP kinase.

Keywords:  Glutamine; Tryptophan hydroxylase 1; mRNA stability Heeyoung Park and Chang-Wook Lee contributed equally as the first author.; p38 MAP kinase

DOI:  https://doi.org/10.1007/s11033-022-07693-7
Mol Syst Biol. 2022 11;18(11): e11033

A functional analysis of 180 cancer cell lines reveals conserved intrinsic metabolic programs.

Sarah Cherkaoui, Stephan Durot, Jenna Bradley, Susan Critchlow, Sebastien Dubuis, Mauro Miguel Masiero, Rebekka Wegmann, Berend Snijder, Alaa Othman, Claus Bendtsen, Nicola Zamboni.

  Cancer cells reprogram their metabolism to support growth and invasion. While previous work has highlighted how single altered reactions and pathways can drive tumorigenesis, it remains unclear how individual changes propagate at the network level and eventually determine global metabolic activity. To characterize the metabolic lifestyle of cancer cells across pathways and genotypes, we profiled the intracellular metabolome of 180 pan-cancer cell lines grown in identical conditions. For each cell line, we estimated activity for 49 pathways spanning the entirety of the metabolic network. Upon clustering, we discovered a convergence into only two major metabolic types. These were functionally confirmed by 13 C-flux analysis, lipidomics, and analysis of sensitivity to perturbations. They revealed that the major differences in cancers are associated with lipid, TCA cycle, and carbohydrate metabolism. Thorough integration of these types with multiomics highlighted little association with genetic alterations but a strong association with markers of epithelial-mesenchymal transition. Our analysis indicates that in absence of variations imposed by the microenvironment, cancer cells adopt distinct metabolic programs which serve as vulnerabilities for therapy.

Keywords:  cancer metabolism; cell lines; metabolic flux; metabolomics; omics

DOI:  https://doi.org/10.15252/msb.202211033
Blood Adv. 2022 Nov 02. pii: bloodadvances.2022007383. [Epub ahead of print]

AKT supports the metabolic fitness of multiple myeloma cells by restricting FOXO activity.

Timon A Bloedjes, Guus de Wilde, Gerarda H Khan, Timothy Cody Ashby, John D Shaughnessy, Fenghuang Zhan, Riekelt H Houtkooper, Richard J Bende, Carel J M van Noesel, Marcel Spaargaren, Jeroen Ej Guikema.

Metabolic alterations are important cancer-associated features that allow cancer cell transformation and their survival under stress conditions. Multiple myeloma (MM) plasma cells show increased glycolysis and oxidative phosphorylation (OXPHOS), characteristics associated with recurrent genetic aberrations that drive the proliferation and survival of MM cells. The protein kinase B/AKT acts as a central node in cellular metabolism and is constitutively active in MM cells. Despite the known role of AKT in modulating cellular metabolism, little is known about the downstream factors of AKT that control the metabolic adaptability of MM cells. Here, we demonstrate that negative regulation of the forkhead box O (FOXO) transcription factors (TF) by AKT is crucial to prevent metabolic shutdown in MM cells, thus contributing to their metabolic adaptability. Our results demonstrate that the expression of several key metabolic genes involved in glycolysis, the tricarboxylic acid (TCA) cycle and OXPHOS, are repressed by FOXO TFs. Moreover, the FOXO-dependent repression of glycolysis- and TCA-associated genes correlates with a favorable prognosis in a large MM patient cohort. Our data suggest that repression of FOXO by AKT is essential to sustain glycolysis and the TCA cycle activity in MM cells, and as such predicts patient survival.

DOI: https://doi.org/10.1182/bloodadvances.2022007383
Annu Rev Pathol. 2022 Nov 02.

Metabolism and Colorectal Cancer.

Joseph C Sedlak, Ömer H Yilmaz, Jatin Roper.

Reprogrammed metabolism is a hallmark of colorectal cancer (CRC). CRC cells are geared toward rapid proliferation, requiring nutrients and the removal of cellular waste in nutrient-poor environments. Intestinal stem cells (ISCs), the primary cell of origin for CRCs, must adapt their metabolism along the adenoma-carcinoma sequence to the unique features of their complex microenvironment that include interactions with intestinal epithelial cells, immune cells, stromal cells, commensal microbes, and dietary components. Emerging evidence implicates modifiable risk factors related to the environment, such as diet, as important in CRC pathogenesis. Here, we focus on describing the metabolism of ISCs, diets that influence CRC initiation, CRC genetics and metabolism, and the tumor microenvironment. The mechanistic links between environmental factors, metabolic adaptations, and the tumor microenvironment in enhancing or supporting CRC tumorigenesis are becoming better understood. Thus, greater knowledge of CRC metabolism holds promise for improved prevention and treatment. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-pathmechdis-031521-041113
Mol Syst Biol. 2022 11;18(11): e11006

Heterogeneity of the cancer cell line metabolic landscape.

David Shorthouse, Jenna Bradley, Susan E Critchlow, Claus Bendtsen, Benjamin A Hall.

  The unravelling of the complexity of cellular metabolism is in its infancy. Cancer-associated genetic alterations may result in changes to cellular metabolism that aid in understanding phenotypic changes, reveal detectable metabolic signatures, or elucidate vulnerabilities to particular drugs. To understand cancer-associated metabolic transformation, we performed untargeted metabolite analysis of 173 different cancer cell lines from 11 different tissues under constant conditions for 1,099 different species using mass spectrometry (MS). We correlate known cancer-associated mutations and gene expression programs with metabolic signatures, generating novel associations of known metabolic pathways with known cancer drivers. We show that metabolic activity correlates with drug sensitivity and use metabolic activity to predict drug response and synergy. Finally, we study the metabolic heterogeneity of cancer mutations across tissues, and find that genes exhibit a range of context specific, and more general metabolic control.

Keywords:  cancer; heterogeneity; metabolomics; mutation

DOI:  https://doi.org/10.15252/msb.202211006
Front Oncol. 2022 ;12 1019949

A novel amino acid metabolism-related gene risk signature for predicting prognosis in clear cell renal cell carcinoma.

Jiaqi Su, Xi Tian, Zihao Zhang, Wenhao Xu, Aihetaimujiang Anwaier, Shiqi Ye, Shuxuan Zhu, Yue Wang, Guohai Shi, Yuanyuan Qu, Hailiang Zhang, Dingwei Ye.

   Background: Renal cancer is one of the most lethal cancers because of its atypical symptoms and metastatic potential. The metabolism of amino acids and their derivatives is essential for cancer cell survival and proliferation. Thus, the construction of the amino acid metabolism-related risk signature might enhance the accuracy of the prognostic model and shed light on the treatments of renal cancers.
Methods: RNA expression and clinical data were downloaded from Santa Cruz (UCSC) Xena, GEO, and ArrayExpress databases. The "DESeq2" package identified the differentially expressed genes. Univariate COX analysis selected prognostic genes related to the metabolism of amino acids. Patients were divided into two clusters using the "ConsensusClusterPlus" package, and the CIBERSORT, ESTIMATE methods were explored to assess the immune infiltrations. The LASSO regression analysis constructed a risk model which was evaluated the prediction accuracy in two independent cohorts. The genomic alterations and drug sensitivity of 18-LASSO-genes were assessed. The differentially expressed genes between two clusters were used to perform functional enrichment analysis and weighted gene co-expression network analysis (WGCNA). Furthermore, external validation of TMEM72 expression was conducted in the FUSCC cohort containing 33 ccRCC patients.
Results: The amino acid metabolism-related genes had significant correlations with prognosis. The patients in Cluster A demonstrated better survival, lower Treg cell proportion, higher ESTIMATE scores, and higher cuproptosis-related gene expressions. Amino acid metabolism-related genes with prognostic values were used to construct a risk model and patients in the low risk group were associated with improved outcomes. The Area Under Curve of the risk model was 0.801, 0.777, and 0.767 at the first, second, and third year respectively. The external validation cohort confirmed the stable prognostic value of the risk model. WGCNA identified four gene modules correlated with immune cell infiltrations and cuproptosis. We found that TMEM72 was downregulated in tumors by using TCGA, GEO datasets (p<0.001) and the FUSCC cohort (p=0.002).
Conclusion: Our study firstly constructed an 18 amino acid metabolism related signature to predict the prognosis in clear cell renal cell carcinoma. We also identified four potential gene modules potentially correlated with cuproptosis and identified TMEM72 downregulation in ccRCC which deserved further studies.

Keywords:  amino acid metabolism; clear cell renal cell carcinoma; cuproptosis; risk signature; transmembrane protein 72

DOI:  https://doi.org/10.3389/fonc.2022.1019949
Trends Cell Biol. 2022 Oct 31. pii: S0962-8924(22)00231-8. [Epub ahead of print]

Plasticity of cancer invasion and energy metabolism.

Maria Parlani, Carolina Jorgez, Peter Friedl.

  Energy deprivation is a frequent adverse event in tumors that is caused by mutations, malperfusion, hypoxia, and nutrition deficit. The resulting bioenergetic stress leads to signaling and metabolic adaptation responses in tumor cells, secures survival, and adjusts migration activity. The kinetic responses of cancer cells to energy deficit were recently identified, including a switch of invasive cancer cells to energy-conservative amoeboid migration and an enhanced capability for distant metastasis. We review the energy programs employed by different cancer invasion modes including collective, mesenchymal, and amoeboid migration, as well as their interconversion in response to energy deprivation, and we discuss the consequences for metastatic escape. Understanding the energy requirements of amoeboid and other dissemination strategies offers rationales for improving therapeutic targeting of metastatic cancer progression.

Keywords:  amoeboid migration; cellular bioenergetics; metabolic stress; migration plasticity

DOI:  https://doi.org/10.1016/j.tcb.2022.09.009