bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2023–08–27
nine papers selected by
Alex Muir, University of Chicago
  1. Myeloperoxidase Alters Lung Cancer Cell Function to Benefit Their Survival.
  2. Editorial: Proteomic and metabolic reprogramming in myeloma cells within the tumor microenvironment.
  3. Preclinical Models and Imaging Modalities of the Tumor Microenvironment in Metastasis.
  4. Dynamic links between mechanical forces and metabolism shape the tumor milieu.
  5. The integrated stress response in cancer progression: a force for plasticity and resistance.
  6. Comprehensive isotopomer analysis of glutamate and aspartate in small tissue samples.
  7. Menin Maintains Cholesterol Content in Colorectal Cancer via Repression of LXR-Mediated Transcription.
  8. Monitoring Metabolic Changes in Response to Chemotherapies in Cancer with Raman Spectroscopy and Metabolomics.
  9. FGF1 supports glycolytic metabolism through the estrogen receptor in endocrine-resistant and obesity-associated breast cancer.
  1. Antioxidants (Basel). 2023 Aug 09. pii: 1587. [Epub ahead of print]12(8):
    Myeloperoxidase Alters Lung Cancer Cell Function to Benefit Their Survival.
    Nejra Cosic-Mujkanovic, Paulina Valadez-Cosmes, Kathrin Maitz, Anna Lueger, Zala N Mihalic, Marah C Runtsch, Melanie Kienzl, Michael J Davies, Christine Y Chuang, Akos Heinemann, Rudolf Schicho, Gunther Marsche, Julia Kargl.
      Myeloperoxidase (MPO) is a neutrophil-derived enzyme that has been recently associated with tumour development. However, the mechanisms by which this enzyme exerts its functions remain unclear. In this study, we investigated whether myeloperoxidase can alter the function of A549 human lung cancer cells. We observed that MPO promoted the proliferation of cancer cells and inhibited their apoptosis. Additionally, it increased the phosphorylation of AKT and ERK. MPO was rapidly bound to and internalized by A549 cells, retaining its enzymatic activity. Furthermore, MPO partially translocated into the nucleus and was detected in the chromatin-enriched fraction. Effects of MPO on cancer cell function could be reduced when MPO uptake was blocked with heparin or upon inhibition of the enzymatic activity with the MPO inhibitor 4-aminobenzoic acid hydrazide (4-ABAH). Lastly, we have shown that tumour-bearing mice treated with 4-ABAH had reduced tumour burden when compared to control mice. Our results highlight the role of MPO as a neutrophil-derived enzyme that can alter the function of lung cancer cells.
    Keywords:  A549 cells; apoptosis; myeloperoxidase (MPO); neutrophil; non-small-cell lung cancer (NSCLC); proliferation
    DOI:  https://doi.org/10.3390/antiox12081587
  2. Front Oncol. 2023 ;13 1264740
    Editorial: Proteomic and metabolic reprogramming in myeloma cells within the tumor microenvironment.
    Enrico Milan, Annamaria Gullà.
      
    Keywords:  IMiDs; bone marrow; metabolism; microenvironment; mitochondria; multiple myeloma; proteasome inhibitors (PI)
    DOI:  https://doi.org/10.3389/fonc.2023.1264740
  3. J Vis Exp. 2023 Mar 17.
    Preclinical Models and Imaging Modalities of the Tumor Microenvironment in Metastasis.
    Sofia Sousa.
      
    DOI:  https://doi.org/10.3791/64933
  4. Curr Opin Cell Biol. 2023 Aug 17. pii: S0955-0674(23)00067-4. [Epub ahead of print]84 102218
    Dynamic links between mechanical forces and metabolism shape the tumor milieu.
    Rebecca Bertolio, Francesco Napoletano, Giannino Del Sal.
      Cell function relies on the spatiotemporal dynamics of metabolic reactions. In all physiopathological processes of tissues, mechanical forces impact the structure and function of membranes, enzymes, organelles and regulators of metabolic gene programs, thus regulating cell metabolism. In turn, metabolic pathways feedback impacts the physical properties of cell and tissues. Hence, metabolism and tissue mechanics are dynamically intertwined and continuously interact. Cancer is akin to an ecosystem, comprising tumor cells and various subpopulations of stromal cells embedded in an altered extracellular matrix. The progression of cancer, from initiation to advanced stage and metastasis, is driven by genetic mutations and crucially influenced by physical and metabolic alterations in the tumor microenvironment. These alterations also play a pivotal role in cancer cells evasion from immune surveillance and in developing resistance to treatments. Here, we highlight emerging evidence showing that mechano-metabolic circuits in cancer and stromal cells regulate multiple processes crucial for tumor progression and discuss potential approaches to improve therapeutic treatments by interfering with these circuits.
    DOI:  https://doi.org/10.1016/j.ceb.2023.102218
  5. Front Oncol. 2023 ;13 1206561
    The integrated stress response in cancer progression: a force for plasticity and resistance.
    Caleb L Lines, Morgan J McGrath, Tanis Dorwart, Crystal S Conn.
      During their quest for growth, adaptation, and survival, cancer cells create a favorable environment through the manipulation of normal cellular mechanisms. They increase anabolic processes, including protein synthesis, to facilitate uncontrolled proliferation and deplete the tumor microenvironment of resources. As a dynamic adaptation to the self-imposed oncogenic stress, cancer cells promptly hijack translational control to alter gene expression. Rewiring the cellular proteome shifts the phenotypic balance between growth and adaptation to promote therapeutic resistance and cancer cell survival. The integrated stress response (ISR) is a key translational program activated by oncogenic stress that is utilized to fine-tune protein synthesis and adjust to environmental barriers. Here, we focus on the role of ISR signaling for driving cancer progression. We highlight mechanisms of regulation for distinct mRNA translation downstream of the ISR, expand on oncogenic signaling utilizing the ISR in response to environmental stresses, and pinpoint the impact this has for cancer cell plasticity during resistance to therapy. There is an ongoing need for innovative drug targets in cancer treatment, and modulating ISR activity may provide a unique avenue for clinical benefit.
    Keywords:  adaptation; cancer; drug resistance; mRNA translation; stress response
    DOI:  https://doi.org/10.3389/fonc.2023.1206561
  6. Cell Metab. 2023 Aug 15. pii: S1550-4131(23)00272-3. [Epub ahead of print]
    Comprehensive isotopomer analysis of glutamate and aspartate in small tissue samples.
    Feng Cai, Divya Bezwada, Ling Cai, Rohit Mahar, Zheng Wu, Mario C Chang, Panayotis Pachnis, Chendong Yang, Sherwin Kelekar, Wen Gu, Bailey Brooks, Bookyung Ko, Hieu S Vu, Thomas P Mathews, Lauren G Zacharias, Misty Martin-Sandoval, Duyen Do, K Celeste Oaxaca, Eunsook S Jin, Vitaly Margulis, Craig R Malloy, Matthew E Merritt, Ralph J DeBerardinis.
      Stable isotopes are powerful tools to assess metabolism. 13C labeling is detected using nuclear magnetic resonance (NMR) spectroscopy or mass spectrometry (MS). MS has excellent sensitivity but generally cannot discriminate among different 13C positions (isotopomers), whereas NMR is less sensitive but reports some isotopomers. Here, we develop an MS method that reports all 16 aspartate and 32 glutamate isotopomers while requiring less than 1% of the sample used for NMR. This method discriminates between pathways that result in the same number of 13C labels in aspartate and glutamate, providing enhanced specificity over conventional MS. We demonstrate regional metabolic heterogeneity within human tumors, document the impact of fumarate hydratase (FH) deficiency in human renal cancers, and investigate the contributions of tricarboxylic acid (TCA) cycle turnover and CO2 recycling to isotope labeling in vivo. This method can accompany NMR or standard MS to provide outstanding sensitivity in isotope-labeling experiments, particularly in vivo.
    Keywords:  aspartate; cancer; glutamate; isotopomer; mass spectrometry; nuclear magnetic resonance; pyruvate carboxylase; stable isotope; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.cmet.2023.07.013
  7. Cancers (Basel). 2023 Aug 16. pii: 4126. [Epub ahead of print]15(16):
    Menin Maintains Cholesterol Content in Colorectal Cancer via Repression of LXR-Mediated Transcription.
    Thomas E Nyul, Keely Beyries, Taylor Hojnacki, Rebecca Glynn, Kayla E Paulosky, Anitej Gedela, Ariana Majer, Lily Altman, Kole H Buckley, Zijie Feng, Kunfeng Sun, Zhicheng Peng, John W Tobias, Xianxin Hua, Bryson W Katona.
       BACKGROUND AND AIMS: Menin is a nuclear scaffold protein that regulates gene transcription in an oftentimes tissue-specific manner. Our previous work showed that menin is over-expressed in colorectal cancer (CRC); however, the full spectrum of menin function in colonic neoplasia remains unclear. Herein, we aimed to uncover novel menin-regulated pathways important for colorectal carcinogenesis.
    METHODS: RNA-Seq analysis identified that menin regulates LXR-target gene expressions in CRC cell lines. Isolated colonic epithelium from Men1f/f;Vil1-Cre and Men1f/f mice was used to validate the results in vivo. Cholesterol content was quantified via an enzymatic assay.
    RESULTS: RNA-Seq analysis in the HT-29 CRC cell line identified that menin inhibition upregulated LXR-target genes, specifically ABCG1 and ABCA1, with protein products that promote cellular cholesterol efflux. Similar results were noted across other CRC cell lines and with different methods of menin inhibition. Consistent with ABCG1 and ABCA1 upregulation, and similarly to LXR agonists, menin inhibition reduced the total cellular cholesterol in both HT-29 and HCT-15 cells. To confirm the effects of menin inhibition in vivo, we assessed Men1f/f;Vil1-Cre mice lacking menin expression in the colonic epithelium. Men1f/f;Vil1-Cre mice were found to have no distinct baseline phenotype compared to control Men1f/f mice. However, similarly to CRC cell lines, Men1f/f;Vil1-Cre mice showed an upregulation of Abcg1 and a reduction in total cellular cholesterol. Promoting cholesterol efflux, either via menin inhibition or LXR activation, was found to synergistically suppress CRC cell growth under cholesterol-depleted conditions and when administered concomitantly with small molecule EGFR inhibitors.
    CONCLUSIONS: Menin represses the transcription of LXR-target genes, including ABCA1 and ABCG1 in the colonic epithelium and CRC. Menin inhibition conversely upregulates LXR-target genes and reduces total cellular cholesterol, demonstrating that menin inhibition may be an important mechanism for targeting cholesterol-dependent pathways in colorectal carcinogenesis.
    Keywords:  ABCA1; ABCG1; LXR; cholesterol; colorectal cancer; menin
    DOI:  https://doi.org/10.3390/cancers15164126
  8. Anal Chem. 2023 Aug 21.
    Monitoring Metabolic Changes in Response to Chemotherapies in Cancer with Raman Spectroscopy and Metabolomics.
    Gabriel Cutshaw, Nora Hassan, Saji Uthaman, Xiaona Wen, Bhuminder Singh, Anwesha Sarkar, Rizia Bardhan.
      Resistance to clinical therapies remains a major barrier in cancer management. There is a critical need for rapid and highly sensitive diagnostic tools that enable early prediction of treatment response to allow accurate clinical decisions. Here, Raman spectroscopy was employed to monitor changes in key metabolites as early predictors of response in KRAS-mutant colorectal cancer (CRC) cells, HCT116, treated with chemotherapies. We show at the single cell level that HCT116 is resistant to cetuximab (CTX), the first-line treatment in CRC, but this resistance can be overcome with pre-sensitization of cells with oxaliplatin (OX). In combination treatment of CTX + OX, sequential delivery of OX followed by CTX rather than simultaneous administration of drugs was observed to be critical for effective therapy. Our results demonstrated that metabolic changes are well aligned to cellular mechanical changes where Young's modulus decreased after effective treatment, indicating that both changes in mechanical properties and metabolism in cells are likely responsible for cancer proliferation. Raman findings were verified with mass spectrometry (MS) metabolomics, and both platforms showed changes in lipids, nucleic acids, and amino acids as predictors of resistance/response. Finally, key metabolic pathways enriched were identified when cells are resistant to CTX but downregulated with effective treatment. This study highlights that drug-induced metabolic changes both at the single cell level (Raman) and ensemble level (MS) have the potential to identify mechanisms of response to clinical cancer therapies.
    DOI:  https://doi.org/10.1021/acs.analchem.3c02073
  9. Breast Cancer Res. 2023 08 22. 25(1): 99
    FGF1 supports glycolytic metabolism through the estrogen receptor in endocrine-resistant and obesity-associated breast cancer.
    Marisol Castillo-Castrejon, Barbara Mensah Sankofi, Stevi Johnson Murguia, Abasi-Ama Udeme, Hoaning Howard Cen, Yi Han Xia, Nisha S Thomas, William L Berry, Kenneth L Jones, Vincent R Richard, Rene P Zahedi, Christoph H Borchers, James D Johnson, Elizabeth A Wellberg.
       BACKGROUND: Obesity increases breast cancer risk and breast cancer-specific mortality, particularly for people with estrogen receptor (ER)-positive tumors. Body mass index (BMI) is used to define obesity, but it may not be the best predictor of breast cancer risk or prognosis on an individual level. Adult weight gain is an independent indicator of breast cancer risk. Our previous work described a murine model of obesity, ER-positive breast cancer, and weight gain and identified fibroblast growth factor receptor (FGFR) as a potential driver of tumor progression. During adipose tissue expansion, the FGF1 ligand is produced by hypertrophic adipocytes as a stimulus to stromal preadipocytes that proliferate and differentiate to provide additional lipid storage capacity. In breast adipose tissue, FGF1 production may stimulate cancer cell proliferation and tumor progression.
    METHODS: We explored the effects of FGF1 on ER-positive endocrine-sensitive and resistant breast cancer and compared that to the effects of the canonical ER ligand, estradiol. We used untargeted proteomics, specific immunoblot assays, gene expression profiling, and functional metabolic assessments of breast cancer cells. The results were validated in tumors from obese mice and breast cancer datasets from women with obesity.
    RESULTS: FGF1 stimulated ER phosphorylation independently of estradiol in cells that grow in obese female mice after estrogen deprivation treatment. Phospho- and total proteomic, genomic, and functional analyses of endocrine-sensitive and resistant breast cancer cells show that FGF1 promoted a cellular phenotype characterized by glycolytic metabolism. In endocrine-sensitive but not endocrine-resistant breast cancer cells, mitochondrial metabolism was also regulated by FGF1. Comparison of gene expression profiles indicated that tumors from women with obesity shared hallmarks with endocrine-resistant breast cancer cells.
    CONCLUSIONS: Collectively, our data suggest that one mechanism by which obesity and weight gain promote breast cancer progression is through estrogen-independent ER activation and cancer cell metabolic reprogramming, partly driven by FGF/FGFR. The first-line treatment for many patients with ER-positive breast cancer is inhibition of estrogen synthesis using aromatase inhibitors. In women with obesity who are experiencing weight gain, locally produced FGF1 may activate ER to promote cancer cell metabolic reprogramming and tumor progression independently of estrogen.
    Keywords:  Adipose; Breast cancer; Estrogen receptor; Fibroblast growth factor; Obesity
    DOI:  https://doi.org/10.1186/s13058-023-01699-0
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