bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2022‒01‒09
thirteen papers selected by
Sreeparna Banerjee
Middle East Technical University
  1. Heterogeneity of glutamine metabolism in acquired-EGFR-TKI-resistant lung cancer.
  2. Autophagy in cancer: The cornerstone during glutamine deprivation.
  3. Glutaminase 2 Knockdown Reduces Hyperammonemia and Associated Lethality of Urea Cycle Disorder Mouse Model.
  4. Mesenchymal Stem Cell-Derived Exosomes Modulate Chondrocyte Glutamine Metabolism to Alleviate Osteoarthritis Progression.
  5. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4.
  6. Glutamine Metabolism Scoring Predicts Prognosis and Therapeutic Resistance in Hepatocellular Carcinoma.
  7. Immunometabolism in bladder cancer microenvironment.
  8. Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness.
  9. Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions.
  10. The Metabolism Symbiosis Between Pancreatic Cancer and Tumor Microenvironment.
  11. Targeting multidrug resistance-associated protein 1 (MRP1)-expressing cancers: Beyond pharmacological inhibition.
  12. Targeting Metabolic Pathways of Myeloid Cells Improves Cancer Immunotherapy.
  13. AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia.
  1. Life Sci. 2022 Jan 03. pii: S0024-3205(21)01261-3. [Epub ahead of print] 120274
    Heterogeneity of glutamine metabolism in acquired-EGFR-TKI-resistant lung cancer.
    Suntae Kim, Jang Su Jeon, Yong June Choi, Ga Hee Baek, Sang Kyum Kim, Keon Wook Kang.
      AIMS: The purpose of this study was to evaluate the heterogeneities of glutamine metabolism in EGFR-TKI-resistant lung cancer cells and its potential as a therapeutic target.MAIN METHODS: Cell proliferation and cell cycle assays was performed by IncuCyte real-time analysis and flow cytometry, respectively. Tumor growth was assessed in xenografts implanted with HCC827 GR. An isotopologue analysis was conducted by LC-MS/MS using 13C-(U)-glutamine labeling to determine the amounts of metabolites. Cellular ATP and mitochondrial oxidative phosphorylation were determined by XFp analysis.
    KEY FINDINGS: We found that the cell growth of the two acquired EGFR-TKI-resistant lung cancer cells lines (HCC827 GR and H292 ER) depends on glutamine. In HCC827 GR, glutamine deficiency caused reduced GSH synthesis and, subsequently, enhanced ROS generation relative to their parental cells, HCC827. On the other hand, in H292 ER, glutamine mainly acted as a carbon source for TCA-cycle intermediates, and its depletion led to reduced mitochondrial ATP production. CB-839, a specific GLS inhibitor, inhibited the latter's conversion of glutamine to glutamate and exerted enhanced anti-proliferating effects on the two acquired EGFR-TKI-resistant lung cancer cell lines versus their parental cell lines. Moreover, oral administration of CB-839 significantly suppressed HCC827 GR tumor growth in the xenograft model.
    SIGNIFICANCE: These findings suggest that glutamine dependency in acquired EGFR-TKI-resistant lung cancer is heterogeneous and that inhibition of glutamine metabolism by CB-839 may serve as a therapeutic tool for acquired EGFR-TKI-resistant lung cancer.
    Keywords:  Acquired EGFR-TKI-resistant lung cancer; CB-839; CB-839 (Telaglenastat; Glutamine metabolism; PubChem CID: 71577426)
    DOI:  https://doi.org/10.1016/j.lfs.2021.120274
  2. Eur J Pharmacol. 2021 Dec 30. pii: S0014-2999(21)00879-7. [Epub ahead of print] 174723
    Autophagy in cancer: The cornerstone during glutamine deprivation.
    Hamza M Fares, Xiaodan Lyu, Xiaoting Xu, Renchao Dong, Muyao Ding, Shichao Mi, Yifan Wang, Xue Li, Shengtao Yuan, Li Sun.
      Over the past two decades, researchers have revealed the crucial functions of glutamine in supporting the hyperproliferation state of cancer cells. Glutamine acts on maintaining high energy production, supporting redox status and amino acid homeostasis. Therefore, cancer cells exhibit excessive uptake of the extracellular glutamine, synthesize it in some cases, and recycle intracellular and extracellular proteins to provide an additional source of glutamine to satisfy the increasing glutamine demand. On the other hand, autophagy's role is still debated regarding tumor initiation and progression. However, most cancer cells urgently need autophagy to overcome the existential threats during glutamine restriction stress. Downstream to various stress pathways induced during such a condition, autophagy is considered an indispensable cytoprotective tool to maintain cell integrity and survival. However, the overactivation of the autophagy process is related to lethal consequences. This review summarized glutamine pathways to control autophagy and highlighted autophagy's primary activation pathways, and discussed the roles during glutamine deprivation.
    Keywords:  Autophagy; Cancer cell metabolism; Glutamine deprivation
    DOI:  https://doi.org/10.1016/j.ejphar.2021.174723
  3. J Inherit Metab Dis. 2022 Jan 06.
    Glutaminase 2 Knockdown Reduces Hyperammonemia and Associated Lethality of Urea Cycle Disorder Mouse Model.
    Xia Mao, Helen Chen, Allen Lin, Sun Kim, Michael E Burczynski, Erqian Na, Gabor Halasz, Mark W Sleeman, Andrew J Murphy, Haruka Okamoto, Xiping Cheng.
      Amino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otcspf-ash ) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: Gls2) or glutamate dehydrogenase 1 (GLUD1, gene name: Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of Gls2 but not Glud1 by AAV8-mediated delivery of a short hairpin RNA in Otcspf-ash mice diminished hyperammonemia and reduced lethality. Knockdown of Gls2 but not Glud1 in Otcspf-ash mice exhibited reduced body weight loss and increased plasma glutamine concentration. These data suggest that Gls2 hepatic knockdown could potentially help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle. This article is protected by copyright. All rights reserved.
    Keywords:  Chronic liver disease; Glutamate dehydrogenase 1; Glutaminase 2; Glutamine; Urea Cycle Disorders; hyperammonemia
    DOI:  https://doi.org/10.1002/jimd.12474
  4. Mediators Inflamm. 2021 ;2021 2979124
    Mesenchymal Stem Cell-Derived Exosomes Modulate Chondrocyte Glutamine Metabolism to Alleviate Osteoarthritis Progression.
    Kai Jiang, Ting Jiang, Yang Chen, Xinzhan Mao.
      Osteoarthritis (OA) had a high incidence in people over 65 years old, and there is currently no drug that could completely cure it. This study is aimed at studying the role of exosomes in regulating glutamine metabolism in the treatment of OA. First, we identified the exosomes extracted from the mouse OA model's bone marrow mesenchymal stem cells (MSC). In vitro, compared with the control group, the cell apoptosis in the OA group increased, while the cell proliferation of the OA group was suppressed. After exosomal treatment, cell apoptosis and cell proliferation were reversed. Inflammatory factors (TNFα, IL-6), glutamine metabolic activity-related proteins (c-MYC, GLS1), glutamine, and GSH/GSSG were increased in the OA group. The overexpression of c-MYC reduced the therapeutic effect of exosomes. At the same time, we found that chondrocyte functional factors (collagen II, Aggrecan) were improved under the treatment of exosomes. However, oe-c-MYC reversed the therapeutic effect of exosomes. In vivo, we found that the running capacity of the mice in the OA group was reduced, and the cartilage tissue was severely damaged. In addition, TNFα, IL-6, and chondrocyte apoptosis increased, while the metabolism of collagen II, Aggrecan, and glutamate decreased in the OA group. After exosomal treatment, the mice's exercise capacity, tissue damage, inflammation, and chondrocyte function were improved, and glutamate metabolism was increased. This study showed that exosomes regulated the level of chondrocyte glutamine metabolism by regulating c-MYC, thereby alleviating OA.
    DOI:  https://doi.org/10.1155/2021/2979124
  5. Open Med (Wars). 2022 ;17(1): 87-95
    Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4.
    Luming Jin, Chaoyang Chen, Lipeng Huang, Qingyu Sun, Liang Bu.
      Long noncoding RNA (lncRNA), specifically the upregulation of lncRNA NR2F1 antisense RNA 1 (NR2F1-AS1), has been involved in the progression of non-small cell lung cancer (NSCLC), but the mechanisms that underlie this remain unclear. In this study, the expression of NR2F1-AS1, miR-363-3p, and SOX4 was assessed in NSCLC cells. A loss-of-function assay was used to measure the tumorigenicity of NSCLC cells. The glycolysis and glutamine metabolism of NSCLC cells was also measured via extracellular acidification rate, consumption of glucose and glutamine, and production of lactate and ATP. The relationships among NR2F1-AS1, miR-363-3p, and SOX4 were detected via dual-luciferase reporter assay. HK-2, GLS1, and SOX4 levels were also analyzed. We found that both NSCLC tissues and cells had higher levels of NR2F1-AS1. Silencing of NR2F1-AS1 inhibited the tumorigenicity of cells in vitro and reduced the glycolysis and glutamine metabolism of NSCLC cells. Regarding its mechanism, NR2F1-AS1 positively regulated the SOX4 level by sponging miR-363-3p. Furthermore, miR-363-3p inhibition or SOX4 overexpression reversed the repressing role of sh-NR2F1-AS1 in the tumorigenicity of NSCLC cells. In summary, NR2F1-AS1 promotes the tumorigenicity of NSCLC cells by regulating miR-363-3p/SOX4.
    Keywords:  NR2F1-AS1; SOX4; glycolysis; miR-363-3p; non-small cell lung cancer
    DOI:  https://doi.org/10.1515/med-2021-0403
  6. Pathol Oncol Res. 2021 ;27 1610075
    Glutamine Metabolism Scoring Predicts Prognosis and Therapeutic Resistance in Hepatocellular Carcinoma.
    Leqian Ying, Meilian Cheng, Yi Lu, Qin Tao, Xiaofeng Chen, Bo Shen, Fen Xiong, Zhangmin Hu, Deqiang Wang, Xiaoqin Li.
      Glutamine metabolism (GM) plays a critical role in hepatocellular carcinoma (HCC); however, a comprehensive methodology to quantify GM activity is still lacking. We developed a transcriptome-based GMScore to evaluate GM activity and investigated the association of GMScore with prognosis and therapeutic resistance. Two independent HCC cohorts with transcriptome data were selected from The Cancer Genome Atlas (TCGA, n = 365) and the International Cancer Genome Consortium (ICGC, n = 231). The expression of 41 GM-associated genes were used to construct and validate GMScore. Several genomic or transcriptomic biomarkers were also estimated. Tumor response to immune checkpoint inhibitors (ICIs) was predicted using the tumor immune dysfunction and exclusion algorithm. GMScore was closely correlated with patient characteristics, including stage, histology grade, alpha-fetoprotein level, and vascular invasion. High GMScore was an independent risk factor for overall survival (OS) in both cohorts (HR = 4.2 and 3.91, both p < 0.001), superior to clinical indices and other biomarkers. High GMScore presented transcriptome features to indicate cell growth advantages and genetic stability, which was associated with poor OS of patients who received transcatheter arterial chemoembolization (TACE). High GMScore was also related to high expression of immune checkpoint genes, increased infiltration of regulatory T cells, and decreased infiltration of M1 macrophages. More importantly, high GMScore indicated poor predicted responses to ICIs, which could be verified in an ICI-treated melanoma cohort. In conclusion, GMScore is a strong prognostic index that may be integrated into existing clinical algorithms. A high GMScore may indicate resistance to TACE and ICIs based on its transcriptome and immune features. Validations using other HCC cohorts, especially ICI-treated HCC cohorts, are necessary.
    Keywords:  glutamine metabolism; hepatocellular carcinoma; immune checkpoint inhibitors; immunotherapy; prognosis; therapeutic resistance
    DOI:  https://doi.org/10.3389/pore.2021.1610075
  7. Endocr Metab Immune Disord Drug Targets. 2022 Jan 04.
    Immunometabolism in bladder cancer microenvironment.
    Mohammad Javad Fattahi, Mohammad Reza Haghshenas, Abbas Ghaderi.
      The initiation and progression of bladder cancer (BC), is dependent on its tumor microenvironment (TME). On the other hand, cancer cells shape and train TME to support their development, respond to treatment and migration in an organism. Immune cells exert key roles in the BC microenvironment and have complex interactions with BC cells. These complicated interplays result in metabolic competition in the TME leading to nutrient deprivation, acidosis, hypoxia and metabolite accumulation, which impair immune cell function. Recent studies have demonstrated that immune cells functions are closely correlated with their metabolism. Immunometabolism describes the functional metabolic alterations that take place within immune cells and the role of these cells in directing metabolism and immune response in tissues or diseases such as cancer. Some molecules and their metabolites in the TME including glucose, fatty acids and amino acids can regulate the phenotype, function and metabolism of immune cells. Hence, here we describe some recent advances in immunometabolism and relate them to BC progression. A profound understanding of the metabolic reprogramming of BC cells and immune cells in the TME will offer novel opportunities for targeted therapies in future.
    Keywords:  Bladder cancer; Immunometabolism; Metabolic Reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.2174/1871530322666220104103905
  8. Cell Metab. 2022 Jan 04. pii: S1550-4131(21)00620-3. [Epub ahead of print]34(1): 90-105.e7
    Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness.
    Pravat Kumar Parida, Mauricio Marquez-Palencia, Vidhya Nair, Akash K Kaushik, Kangsan Kim, Jessica Sudderth, Eduardo Quesada-Diaz, Ambar Cajigas, Vamsidhara Vemireddy, Paula I Gonzalez-Ericsson, Melinda E Sanders, Bret C Mobley, Kenneth Huffman, Sunati Sahoo, Prasanna Alluri, Cheryl Lewis, Yan Peng, Robert M Bachoo, Carlos L Arteaga, Ariella B Hanker, Ralph J DeBerardinis, Srinivas Malladi.
      HER2+ breast cancer patients are presented with either synchronous (S-BM), latent (Lat), or metachronous (M-BM) brain metastases. However, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ remains unknown. Here, employing brain metastatic models, we show that metabolic diversity and plasticity within brain-tropic cells determine metastatic fitness. Lactate secreted by aggressive metastatic cells or lactate supplementation to mice bearing Lat cells limits innate immunosurveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immunosurveillance, oxidize glutamine, and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Moreover, xCT expression is significantly higher in matched M-BM brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Inhibiting xCT function attenuates residual disease and recurrence in these preclinical models.
    Keywords:  HER2; breast cancer brain metastasis; immune surveillance; late recurrences; metabolism; metastasis; metastatic dormancy; metastatic latency; redox homeostasis; relapse
    DOI:  https://doi.org/10.1016/j.cmet.2021.12.001
  9. BMC Cancer. 2022 Jan 06. 22(1): 39
    Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions.
    Hosein Rostamian, Mohammad Khakpoor-Koosheh, Leila Jafarzadeh, Elham Masoumi, Keyvan Fallah-Mehrjardi, Mohammad Javad Tavassolifar, John M Pawelek, Hamid Reza Mirzaei, Jamshid Hadjati.
      BACKGROUND: Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing the activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve immunosurveillance and tumor growth regulation. Dichloroacetate (DCA) limits the tumor-derived lactic acid by altering the cancer cell metabolism. In this study, the effects of lactic acid on the activation and function of T cells, were analyzed by assessing T cell proliferation, cytokine production and the cellular redox state of T cells. We examined the redox system in T cells by analyzing the intracellular level of reactive oxygen species (ROS), superoxide and glutathione and gene expression of some proteins that have a role in the redox system. Then we co-cultured DCA-treated tumor cells with T cells to examine the effect of reduced tumor-derived lactic acid on proliferative response, cytokine secretion and viability of T cells.RESULT: We found that lactic acid could dampen T cell function through suppression of T cell proliferation and cytokine production as well as restrain the redox system of T cells by decreasing the production of oxidant and antioxidant molecules. DCA decreased the concentration of tumor lactic acid by manipulating glucose metabolism in tumor cells. This led to increases in T cell proliferation and cytokine production and also rescued the T cells from apoptosis.
    CONCLUSION: Taken together, our results suggest accumulation of lactic acid in the tumor microenvironment restricts T cell responses and could prevent the success of T cell therapy. DCA supports anti-tumor responses of T cells by metabolic reprogramming of tumor cells.
    Keywords:  Cancer; Dichloroacetate, Immunotherapy; Lactic acid; Metabolism; T cell
    DOI:  https://doi.org/10.1186/s12885-021-09151-2
  10. Front Oncol. 2021 ;11 759376
    The Metabolism Symbiosis Between Pancreatic Cancer and Tumor Microenvironment.
    Ying Li, Ju Zhang, Jie Xu, Shanglong Liu.
      Complex interactions occur between tumor cells and the tumor microenvironment. Studies have focused on the mechanism of metabolic symbiosis between tumors and the tumor microenvironment. During tumor development, the metabolic pattern undergoes significant changes, and the optimal metabolic mode of the tumor is selected on the basis of its individual environment. Tumor cells can adapt to a specific microenvironment through metabolic adjustment to achieve compatibility. In this study, the effects of tumor glucose metabolism, lipid metabolism, and amino acid metabolism on the tumor microenvironment and related mechanisms were reviewed. Selective targeting of tumor cell metabolic reprogramming is an attractive direction for tumor therapy. Understanding the mechanism of tumor metabolic adaptation and determining the metabolism symbiosis mechanism between tumor cells and the surrounding microenvironment may provide a new approach for treatment, which is of great significance for accelerating the development of targeted tumor metabolic drugs and administering individualized tumor metabolic therapy.
    Keywords:  crosstalk; metabolic remodeling; metabolism symbiosis; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.759376
  11. Drug Resist Updat. 2021 Dec 10. pii: S1368-7646(21)00055-8. [Epub ahead of print] 100795
    Targeting multidrug resistance-associated protein 1 (MRP1)-expressing cancers: Beyond pharmacological inhibition.
    Kimberley M Hanssen, Michelle Haber, Jamie I Fletcher.
      Resistance to chemotherapy remains one of the most significant obstacles to successful cancer treatment. While inhibiting drug efflux mediated by ATP-binding cassette (ABC) transporters is a seemingly attractive and logical approach to combat multidrug resistance (MDR), small molecule inhibition of ABC transporters has so far failed to confer clinical benefit, despite considerable efforts by medicinal chemists, biologists, and clinicians. The long-sought treatment to eradicate cancers displaying ABC transporter overexpression may therefore lie within alternative targeting strategies. When aberrantly expressed, the ABC transporter multidrug resistance-associated protein 1 (MRP1, ABCC1) confers MDR, but can also shift cellular redox balance, leaving the cell vulnerable to select agents. Here, we explore the physiological roles of MRP1, the rational for targeting this transporter in cancer, the development of small molecule MRP1 inhibitors, and the most recent developments in alternative therapeutic approaches for targeting cancers with MRP1 overexpression. We discuss approaches that extend beyond simple MRP1 inhibition by exploiting the collateral sensitivity to glutathione depletion and ferroptosis, the rationale for targeting the shared transcriptional regulators of both MRP1 and glutathione biosynthesis, advances in gene silencing, and new molecules that modulate transporter activity to the detriment of the cancer cell. These strategies illustrate promising new approaches to address multidrug resistant disease that extend beyond the simple reversal of MDR and offer exciting routes for further research.
    Keywords:  ABCC1; Cancer; Ferroptosis; Glutathione; Inhibitor; KEAP1; MDR; MRP1; Modulator; NRF2; Nanomedicine; Oxidative stress
    DOI:  https://doi.org/10.1016/j.drup.2021.100795
  12. Front Cell Dev Biol. 2021 ;9 747863
    Targeting Metabolic Pathways of Myeloid Cells Improves Cancer Immunotherapy.
    Jianying Li, Chelsea Bolyard, Gang Xin, Zihai Li.
      Tumor-infiltrating myeloid cells are a prominent pro-tumorigenic immune cell population that limit host anti-tumor immunity and present a significant obstacle for many cancer immunotherapies. Targeting the mechanisms regulating myeloid cell function within the tumor microenvironment may overcome immunotherapy resistance in some cancers. Recent discoveries in the emerging field of immunometabolism reveal that the metabolic profiles of intratumoral myeloid cells are rewired to adapt to the nutrition-limited tumor microenvironment, and this shapes their pro-tumor phenotypes. Interestingly, metabolic modulation can shift these myeloid cells toward the immune-stimulating anti-tumor phenotype. In this review, we will highlight the roles of specific metabolic pathways in the activation and function of myeloid cells, and discuss the therapeutic value of metabolically reprogramming myeloid cells to augment and improve outcomes with cancer immunotherapy.
    Keywords:  immunometabolism; immunotherapy; myeloid cells; myeloid-derived suppressor cells; tumor-associated dendritic cells; tumor-associated macrophages; tumor-associated neutrophils; tumor-infiltrating myeloid cells
    DOI:  https://doi.org/10.3389/fcell.2021.747863
  13. Cell Rep. 2022 Jan 04. pii: S2211-1247(21)01701-0. [Epub ahead of print]38(1): 110197
    AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia.
    Adrien Grenier, Laury Poulain, Johanna Mondesir, Arnaud Jacquel, Claudie Bosc, Lucille Stuani, Sarah Mouche, Clement Larrue, Ambrine Sahal, Rudy Birsen, Victoria Ghesquier, Justine Decroocq, Fetta Mazed, Mireille Lambert, Mamy Andrianteranagna, Benoit Viollet, Patrick Auberger, Andrew A Lane, Pierre Sujobert, Didier Bouscary, Jean-Emmanuel Sarry, Jerome Tamburini.
      AMP-activated protein kinase (AMPK) regulates the balance between cellular anabolism and catabolism dependent on energy resources to maintain proliferation and survival. Small-compound AMPK activators show anti-cancer activity in preclinical models. Using the direct AMPK activator GSK621, we show that the unfolded protein response (UPR) is activated by AMPK in acute myeloid leukemia (AML) cells. Mechanistically, the UPR effector protein kinase RNA-like ER kinase (PERK) represses oxidative phosphorylation, tricarboxylic acid (TCA) cycle, and pyrimidine biosynthesis and primes the mitochondrial membrane to apoptotic signals in an AMPK-dependent manner. Accordingly, in vitro and in vivo studies reveal synergy between the direct AMPK activator GSK621 and the Bcl-2 inhibitor venetoclax. Thus, selective AMPK-activating compounds kill AML cells by rewiring mitochondrial metabolism that primes mitochondria to apoptosis by BH3 mimetics, holding therapeutic promise in AML.
    Keywords:  AML; AMPK; GSK621; PERK; mitochondrial apoptosis; unfolded protein response; venetoclax
    DOI:  https://doi.org/10.1016/j.celrep.2021.110197
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