bims-mascan 2020-03-01 papers

bims-mascan

Biomed News

on Mass spectrometry in cancer research

Issue of 2020‒03‒01
thirteen papers selected by
Giovanny Rodriguez Blanco
The Beatson Institute for Cancer Research

Lipidomic identification of plasma lipids associated with pain behaviour and pathology in a mouse model of osteoarthritis.
Absolute Quantification of the Central Carbon Metabolome in Eight Commonly Applied Prokaryotic and Eukaryotic Model Systems.
NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview.
Regulation of branched-chain amino acid metabolism by hypoxia-inducible factor in glioblastoma.
Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death.
Metabolic Profiling of the Cerebrospinal Fluid in Pediatric Epilepsy.
Metabolome analysis reveals excessive glycolysis via PI3K/AKT/mTOR and RAS/MAPK signaling in methotrexate-resistant primary CNS lymphoma-derived cells.
Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure.
Ferroptosis: Final destination for cancer?
Lipid availability determines fate of skeletal progenitor cells via SOX9.
Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition.
Untargeted metabolomics links glutathione to bacterial cell cycle progression.
CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer.

Metabolomics. 2020 Feb 27. 16(3): 32

Lipidomic identification of plasma lipids associated with pain behaviour and pathology in a mouse model of osteoarthritis.

P Pousinis, P R W Gowler, J J Burston, C A Ortori, V Chapman, D A Barrett.

  INTRODUCTION: Osteoarthritis (OA) is the most common form of joint disease, causing pain and disability. Previous studies have demonstrated the role of lipid mediators in OA pathogenesis.OBJECTIVES: To explore potential alterations in the plasma lipidomic profile in an established mouse model of OA, with a view to identification of potential biomarkers of pain and/or pathology.
METHODS: Pain behaviour was assessed following destabilisation of the medial meniscus (DMM) model of OA (n = 8 mice) and compared to sham controls (n = 7). Plasma and knee joints were collected at 16 weeks post-surgery. Plasma samples were analysed using ultra-high performance liquid chromatography accurate mass high resolution mass spectrometry (UHPLC-HR-MS) to identify potential differences in the lipidome, using multivariate and univariate statistical analyses. Correlations between pain behaviour, joint pathology and levels of lipids were investigated.
RESULTS: 24 lipids, predominantly from the lipid classes of cholesterol esters (CE), fatty acids (FA), phosphatidylcholines (PC), N-acylethanolamines (NAE) and sphingomyelins (SM), were differentially expressed in DMM plasma compared to sham plasma. Six of these lipids which were increased in the DMM model were identified as CE(18:2), CE(20:4), CE(22:6), PC(18:0/18:2), PC(38:7) and SM(d34:1). CEs were positively correlated with pain behaviour and all six lipid species were positively correlated with cartilage damage. Pathways shown to be involved in altered lipid homeostasis in OA were steroid biosynthesis and sphingolipid metabolism.
CONCLUSION: We identify plasma lipid species associated with pain and/or pathology in a DMM model of OA.

Keywords:  Destabilisation of the medial meniscus; LC–MS lipidomics; Osteoarthritis; Pain

DOI:  https://doi.org/10.1007/s11306-020-01652-8
Metabolites. 2020 Feb 19. pii: E74. [Epub ahead of print]10(2):

Absolute Quantification of the Central Carbon Metabolome in Eight Commonly Applied Prokaryotic and Eukaryotic Model Systems.

Lisa M Røst, Lilja Brekke Thorfinnsdottir, Kanhaiya Kumar, Katsuya Fuchino, Ida Eide Langørgen, Zdenka Bartosova, Kåre Andre Kristiansen, Per Bruheim.

  Absolute quantification of intracellular metabolite pools is a prerequisite for modeling and in-depth biological interpretation of metabolomics data. It is the final step of an elaborate metabolomics workflow, with challenges associated with all steps-from sampling to quantifying the physicochemically diverse metabolite pool. Chromatographic separation combined with mass spectrometric (MS) detection is the superior platform for high coverage, selective, and sensitive detection of metabolites. Herein, we apply our quantitative MS-metabolomics workflow to measure and present the central carbon metabolome of a panel of commonly applied biological model systems. The workflow includes three chromatographic methods combined with isotope dilution tandem mass spectrometry to allow for absolute quantification of 68 metabolites of glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle, and the amino acid and (deoxy) nucleoside pools. The biological model systems; Bacillus subtilis, Saccharomyces cerevisiae, two microalgal species, and four human cell lines were all cultured in commonly applied culture media and sampled in exponential growth phase. Both literature and databases are scarce with comprehensive metabolite datasets, and existing entries range over several orders of magnitude. The workflow and metabolite panel presented herein can be employed to expand the list of reference metabolomes, as encouraged by the metabolomics community, in a continued effort to develop and refine high-quality quantitative metabolomics workflows.

Keywords:  B. subtilis; S. cerevisiae; absolute quantification; central carbon metabolism; human cell lines; intracellular metabolite pools; metabolome database; microalgae; tandem mass spectrometry; targeted metabolite profiling

DOI:  https://doi.org/10.3390/metabo10020074
Biomolecules. 2020 Feb 26. pii: E358. [Epub ahead of print]10(3):

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview.

Alvinsyah Adhityo Pramono, Gulam M Rather, Herry Herman, Keri Lestari, Joseph R Bertino.

  Actively proliferating cancer cells require sufficient amount of NADH and NADPH for biogenesis and to protect cells from the detrimental effect of reactive oxygen species. As both normal and cancer cells share the same NAD biosynthetic and metabolic pathways, selectively lowering levels of NAD(H) and NADPH would be a promising strategy for cancer treatment. Targeting nicotinamide phosphoribosyltransferase (NAMPT), a rate limiting enzyme of the NAD salvage pathway, affects the NAD and NADPH pool. Similarly, lowering NADPH by mutant isocitrate dehydrogenase 1/2 (IDH1/2) which produces D-2-hydroxyglutarate (D-2HG), an oncometabolite that downregulates nicotinate phosphoribosyltransferase (NAPRT) via hypermethylation on the promoter region, results in epigenetic regulation. NADPH is used to generate D-2HG, and is also needed to protect dihydrofolate reductase, the target for methotrexate, from degradation. NAD and NADPH pools in various cancer types are regulated by several metabolic enzymes, including methylenetetrahydrofolate dehydrogenase, serine hydroxymethyltransferase, and aldehyde dehydrogenase. Thus, targeting NAD and NADPH synthesis under special circumstances is a novel approach to treat some cancers. This article provides the rationale for targeting the key enzymes that maintain the NAD/NADPH pool, and reviews preclinical studies of targeting these enzymes in cancers.

Keywords:  IDH mutation; NAD/NADPH pool; NADK inhibitor; NAMPT inhibitor; dihydrofolate reductase

DOI:  https://doi.org/10.3390/biom10030358
Cell Mol Life Sci. 2020 Feb 22.

Regulation of branched-chain amino acid metabolism by hypoxia-inducible factor in glioblastoma.

Bo Zhang, Yan Chen, Xiaolei Shi, Mi Zhou, Lei Bao, Kimmo J Hatanpaa, Toral Patel, Ralph J DeBerardinis, Yingfei Wang, Weibo Luo.

  Hypoxia-inducible factors (HIFs) mediate metabolic reprogramming in response to hypoxia. However, the role of HIFs in branched-chain amino acid (BCAA) metabolism remains unknown. Here we show that hypoxia upregulates mRNA and protein levels of the BCAA transporter LAT1 and the BCAA metabolic enzyme BCAT1, but not their paralogs LAT2-4 and BCAT2, in human glioblastoma (GBM) cell lines as well as primary GBM cells. Hypoxia-induced LAT1 protein upregulation is mediated by both HIF-1 and HIF-2 in GBM cells. Although both HIF-1α and HIF-2α directly bind to the hypoxia response element at the first intron of the human BCAT1 gene, HIF-1α is exclusively responsible for hypoxia-induced BCAT1 expression in GBM cells. Knockout of HIF-1α and HIF-2α significantly reduces glutamate labeling from BCAAs in GBM cells under hypoxia, which provides functional evidence for HIF-mediated reprogramming of BCAA metabolism. Genetic or pharmacological inhibition of BCAT1 inhibits GBM cell growth under hypoxia. Together, these findings uncover a previously unrecognized HIF-dependent metabolic pathway that increases GBM cell growth under conditions of hypoxic stress.

Keywords:  Branched-chain amino acid; Gene regulation; Glioblastoma; Hypoxia; Hypoxia-inducible factor; Metabolism

DOI:  https://doi.org/10.1007/s00018-020-03483-1
Cancer Cell Int. 2020 ;20 52

Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death.

Hannah Maria Baumert, Eric Metzger, Matthias Fahrner, Julie George, Roman K Thomas, Oliver Schilling, Roland Schüle.

  Background: Lung cancer is the leading cause of cancer related death worldwide. Over the past 15 years no major improvement of survival rates could be accomplished. The recently discovered histone methyltransferase KMT9 that acts as epigenetic regulator of prostate tumor growth has now raised hopes of enabling new cancer therapies. In this study, we aimed to identify the function of KMT9 in lung cancer.Methods: We unraveled the KMT9 transcriptome and proteome in A549 lung adenocarcinoma cells using RNA-Seq and mass spectrometry and linked them with functional cell culture, real-time proliferation and flow cytometry assays.
Results: We show that KMT9α and -β subunits of KMT9 are expressed in lung cancer tissue and cell lines. Importantly, high levels of KMT9α correlate with poor patient survival. We identified 460 genes that are deregulated at the RNA and protein level upon knock-down of KMT9α in A549 cells. These genes cluster with proliferation, cell cycle and cell death gene sets as well as with subcellular organelles in gene ontology analysis. Knock-down of KMT9α inhibits lung cancer cell proliferation and induces non-apoptotic cell death in A549 cells.
Conclusions: The novel histone methyltransferase KMT9 is crucial for proliferation and survival of lung cancer cells harboring various mutations. Small molecule inhibitors targeting KMT9 therefore should be further examined as potential milestones in modern epigenetic lung cancer therapy.

Keywords:  A549; Epigenetics; Histone methyltransferase; KMT9; Lung cancer; Non-small cell lung cancer; Proteomics; Transcriptomics

DOI:  https://doi.org/10.1186/s12935-020-1141-2
Acta Med Okayama. 2020 Feb;74(1): 65-72

Metabolic Profiling of the Cerebrospinal Fluid in Pediatric Epilepsy.

Tomoyuki Akiyama, Daisuke Saigusa, Yuki Hyodo, Keiko Umeda, Reina Saijo, Seizo Koshiba, Katsuhiro Kobayashi.

  To characterize metabolic profiles within the central nervous system in epilepsy, we performed gas chromatography-tandem mass spectrometry (GC-MS/MS)-based metabolome analysis of the cerebrospinal fluid (CSF) in pediatric patients with and without epilepsy. The CSF samples obtained from 64 patients were analyzed by GC-MS/MS. Multivariate analyses were performed for two age groups, 0-5 years of age and 6-17 years of age, to elucidate the effects of epilepsy and antiepileptic drugs on the metabolites. In patients aged 0-5 years (22 patients with epilepsy, 13 without epilepsy), epilepsy patients had reduced 2-ketoglutaric acid and elevated pyridoxamine and tyrosine. In patients aged 6-17 years (12 with epilepsy, 17 without epilepsy), epilepsy patients had reduced 1,5-anhydroglucitol. Valproic acid was associated with elevated 2-aminobutyric acid, 2-ketoisocaproic acid, 4-hydroxyproline, acetylglycine, methionine, N-acetylserine, and serine. Reduced energy metabolism and alteration of vitamin B6 metabolism may play a role in epilepsy in young children. The roles of 1,5-anhydroglucitol in epilepsy in older children and in levetiracetam and zonisamide treatment remain to be explained. Valproic acid influenced the levels of amino acids and related metabolites involved in the metabolism of serine, methionine, and leucine.

Keywords:  antiepileptic drugs; gas chromatography-tandem mass spectrometry; metabolome analysis; metabolomics

DOI:  https://doi.org/10.18926/AMO/57955
Clin Cancer Res. 2020 Feb 27. pii: clincanres.3851.2018. [Epub ahead of print]

Metabolome analysis reveals excessive glycolysis via PI3K/AKT/mTOR and RAS/MAPK signaling in methotrexate-resistant primary CNS lymphoma-derived cells.

Yasuo Takashima, Azusa Hayano, Ryuya Yamanaka.

PURPOSE: Metabolome analysis is an emerging method that provides insight into intracellular and physiological responses. Methotrexate (MTX) is an antifolate that suppresses DNA syntheses by inhibiting dihydrofolate reductase. High-dose MTX treatment with deferred radiotherapy is a standard protocol in primary central nervous system lymphoma (PCNSL) treatments. However, most cases come to relapse-acquired resistance, in which the role of metabolic pathways are largely unknown.METHODS: Metabolome analysis in MTX-resistant PCNSL-derived cells (designated as TK-MTX and HKBML-MTX) was performed to detect alternative metabolites and pathways.
RESULTS: The metabolomic analyses using capillary electrophoresis-time-of-flight mass spectrometry detected 188 and 169 peaks in TK and HKBML-derived cells, respectively, including suppression of central carbon metabolism, lipid metabolism, nucleic acid metabolism, urea cycle, branched-chain and aromatic amino acids, and coenzyme metabolism. Particularly, whole suppressive metabolic pathways were demonstrated in TK-MTX, whereas HKBML-MTX indicated partially enhanced pathways of the urea cycle, amino acid metabolism, and coenzyme metabolism. Reciprocally detected metabolites for glycolysis, including induced glucose and reduced glycogen, and induced lactate and reduced pyruvate, in addition to increased lactate dehydrogenase activity, which is involved in Warburg effect. Thereby, ATP was increased in both MTX-resistant PCNSL-derived cells. Further, we specifically found that PI3K/AKT/mTOR and RAS/MAPK signaling pathways were activated in TK-MTX but not in HKBML-MTX by growth rate with inhibitors and gene expression analysis, suggestive of cell type-specific MTX-resistant metabolic pathways.
CONCLUSIONS: These results can help us understand targeted therapies with selective anticancer drugs in recurrent CNS lymphoma-acquired resistance against MTX.

DOI: https://doi.org/10.1158/1078-0432.CCR-18-3851
Cell Death Dis. 2020 Feb 24. 11(2): 144

Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure.

Naoya Yamada, Tadayoshi Karasawa, Hiroaki Kimura, Sachiko Watanabe, Takanori Komada, Ryo Kamata, Ariunaa Sampilvanjil, Junya Ito, Kiyotaka Nakagawa, Hiroshi Kuwata, Shuntaro Hara, Koichi Mizuta, Yasunaru Sakuma, Naohiro Sata, Masafumi Takahashi.

Acetaminophen (APAP) overdose is a common cause of drug-induced acute liver failure. Although hepatocyte cell death is considered to be the critical event in APAP-induced hepatotoxicity, the underlying mechanism remains unclear. Ferroptosis is a newly discovered type of cell death that is caused by a loss of cellular redox homeostasis. As glutathione (GSH) depletion triggers APAP-induced hepatotoxicity, we investigated the role of ferroptosis in a murine model of APAP-induced acute liver failure. APAP-induced hepatotoxicity (evaluated in terms of ALT, AST, and the histopathological score), lipid peroxidation (4-HNE and MDA), and upregulation of the ferroptosis maker PTGS2 mRNA were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1). Fer-1 treatment also completely prevented mortality induced by high-dose APAP. Similarly, APAP-induced hepatotoxicity and lipid peroxidation were prevented by the iron chelator deferoxamine. Using mass spectrometry, we found that lipid peroxides derived from n-6 fatty acids, mainly arachidonic acid, were elevated by APAP, and that auto-oxidation is the predominant mechanism of APAP-derived lipid oxidation. APAP-induced hepatotoxicity was also prevented by genetic inhibition of acyl-CoA synthetase long-chain family member 4 or α-tocopherol supplementation. We found that ferroptosis is responsible for APAP-induced hepatocyte cell death. Our findings provide new insights into the mechanism of APAP-induced hepatotoxicity and suggest that ferroptosis is a potential therapeutic target for APAP-induced acute liver failure.

DOI: https://doi.org/10.1038/s41419-020-2334-2
Cell Prolif. 2020 Feb 25. e12761

Ferroptosis: Final destination for cancer?

Zeng Ye, Wensheng Liu, Qifeng Zhuo, Qiangsheng Hu, Mengqi Liu, Qiqing Sun, Zheng Zhang, Guixiong Fan, Wenyan Xu, Shunrong Ji, Xianjun Yu, Yi Qin, Xiaowu Xu.

  Ferroptosis is a recently defined, non-apoptotic, regulated cell death (RCD) process that comprises abnormal metabolism of cellular lipid oxides catalysed by iron ions or iron-containing enzymes. In this process, a variety of inducers destroy the cell redox balance and produce a large number of lipid peroxidation products, eventually triggering cell death. However, in terms of morphology, biochemistry and genetics, ferroptosis is quite different from apoptosis, necrosis, autophagy-dependent cell death and other RCD processes. A growing number of studies suggest that the relationship between ferroptosis and cancer is extremely complicated and that ferroptosis promises to be a novel approach for the cancer treatment. This article primarily focuses on the mechanism of ferroptosis and discusses the potential application of ferroptosis in cancer therapy.

Keywords:  GPx4; cancer therapy; ferroptosis; lipid peroxidation

DOI:  https://doi.org/10.1111/cpr.12761
Nature. 2020 Feb 26.

Lipid availability determines fate of skeletal progenitor cells via SOX9.

Nick van Gastel, Steve Stegen, Guy Eelen, Sandra Schoors, Aurélie Carlier, Veerle W Daniëls, Ninib Baryawno, Dariusz Przybylski, Maarten Depypere, Pieter-Jan Stiers, Dennis Lambrechts, Riet Van Looveren, Sophie Torrekens, Azeem Sharda, Patrizia Agostinis, Diether Lambrechts, Frederik Maes, Johan V Swinnen, Liesbet Geris, Hans Van Oosterwyck, Bernard Thienpont, Peter Carmeliet, David T Scadden, Geert Carmeliet.

The avascular nature of cartilage makes it a unique tissue1-4, but whether and how the absence of nutrient supply regulates chondrogenesis remain unknown. Here we show that obstruction of vascular invasion during bone healing favours chondrogenic over osteogenic differentiation of skeletal progenitor cells. Unexpectedly, this process is driven by a decreased availability of extracellular lipids. When lipids are scarce, skeletal progenitors activate forkhead box O (FOXO) transcription factors, which bind to the Sox9 promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life. Our results define lipid scarcity as an important determinant of chondrogenic commitment, reveal a role for FOXO transcription factors during lipid starvation, and identify SOX9 as a critical metabolic mediator. These data highlight the importance of the nutritional microenvironment in the specification of skeletal cell fate.

DOI: https://doi.org/10.1038/s41586-020-2050-1
Cell Rep. 2020 Feb 25. pii: S2211-1247(20)30105-4. [Epub ahead of print]30(8): 2729-2742.e4

Macropinocytosis Renders a Subset of Pancreatic Tumor Cells Resistant to mTOR Inhibition.

Evdokia Michalopoulou, Francesca R Auciello, Vinay Bulusu, David Strachan, Andrew D Campbell, Jacqueline Tait-Mulder, Saadia A Karim, Jennifer P Morton, Owen J Sansom, Jurre J Kamphorst.

  Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in KRAS. Additionally, the tumor suppressor PTEN is lost in ∼10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and phosphatidylinositol 3-kinase (PI3K) cause divergent metabolic phenotypes individually, how they synergize to promote tumor metabolic alterations and dependencies remains unknown. We show that in KRAS-driven murine PDAC cells, loss of Pten strongly enhances both mTOR signaling and macropinocytosis. Protein scavenging alleviates sensitivity to mTOR inhibition by rescuing AKT phosphorylation at serine 473 and consequently cell proliferation. Combined inhibition of mTOR and lysosomal processing of internalized protein eliminates the macropinocytosis-mediated resistance. Our results indicate that mTORC2, rather than mTORC1, is an important regulator of protein scavenging and that protein-mediated resistance could explain the lack of effectiveness of mTOR inhibitors in certain genetic backgrounds. Concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach.

Keywords:  AKT; cancer metabolism; mTORC2; macropinocytosis; metabolic scavenging; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1016/j.celrep.2020.01.080
Nat Metab. 2020 Feb;2(2): 153-166

Untargeted metabolomics links glutathione to bacterial cell cycle progression.

Johannes Hartl, Patrick Kiefer, Andreas Kaczmarczyk, Maximilian Mittelviefhaus, Fabian Meyer, Thomas Vonderach, Bodo Hattendorf, Urs Jenal, Julia A Vorholt.

Cell cycle progression requires the coordination of cell growth, chromosome replication, and division. Consequently, a functional cell cycle must be coupled with metabolism. However, direct measurements of metabolome dynamics remained scarce, in particular in bacteria. Here, we describe an untargeted metabolomics approach with synchronized Caulobacter crescentus cells to monitor the relative abundance changes of ~400 putative metabolites as a function of the cell cycle. While the majority of metabolite pools remains homeostatic, ~14% respond to cell cycle progression. In particular, sulfur metabolism is redirected during the G1-S transition, and glutathione levels periodically change over the cell cycle with a peak in late S phase. A lack of glutathione perturbs cell size by uncoupling cell growth and division through dysregulation of KefB, a K+/H+ antiporter. Overall, we here describe the impact of the C. crescentus cell cycle progression on metabolism, and in turn relate glutathione and potassium homeostasis to timely cell division.

DOI: https://doi.org/10.1038/s42255-019-0166-0
Mol Cancer. 2020 Feb 27. 19(1): 43

CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer.

Haiyang Zhang, Ting Deng, Rui Liu, Tao Ning, Haiou Yang, Dongying Liu, Qiumo Zhang, Dan Lin, Shaohua Ge, Ming Bai, Xinyi Wang, Le Zhang, Hongli Li, Yuchong Yang, Zhi Ji, Hailong Wang, Guoguang Ying, Yi Ba.

  BACKGROUND: Ferroptosis is a novel mode of non-apoptotic cell death induced by build-up of toxic lipid peroxides (lipid-ROS) in an iron dependent manner. Cancer-associated fibroblasts (CAFs) support tumor progression and drug resistance by secreting various bioactive substances, including exosomes. Yet, the role of CAFs in regulating lipid metabolism as well as ferroptosis of cancer cells is still unexplored and remains enigmatic.METHODS: Ferroptosis-related genes in gastric cancer (GC) were screened by using mass spectrum; exosomes were isolated by ultra-centrifugation and CAF secreted miRNAs were determined by RT-qPCR. Erastin was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring lipid-ROS, cell viability and mitochondrial membrane potential.
RESULTS: Here, we provide clinical evidence to show that arachidonate lipoxygenase 15 (ALOX15) is closely related with lipid-ROS production in gastric cancer, and that exosome-miR-522 serves as a potential inhibitor of ALOX15. By using primary stromal cells and cancer cells, we prove that exosome-miR-522 is mainly derived from CAFs in tumor microenvironment. Moreover, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was found to mediate miR-522 packing into exosomes, and ubiquitin-specific protease 7 (USP7) stabilizes hnRNPA1 through de-ubiquitination. Importantly, cisplatin and paclitaxel promote miR-522 secretion from CAFs by activating USP7/hnRNPA1 axis, leading to ALOX15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately result in decreased chemo-sensitivity.
CONCLUSIONS: The present study demonstrates that CAFs secrete exosomal miR-522 to inhibit ferroptosis in cancer cells by targeting ALOX15 and blocking lipid-ROS accumulation. The intercellular pathway, comprising USP7, hnRNPA1, exo-miR-522 and ALOX15, reveals new mechanism of acquired chemo-resistance in GC.

Keywords:  Cancer-associated fibroblasts; Exosomes; Ferroptosis; GC; miR-522

DOI:  https://doi.org/10.1186/s12943-020-01168-8