bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023–12–24
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Merlin/NF2 regulates SLC7A11/xCT expression and cell viability under glucose deprivation at high cell density in glioblastoma cells.
  2. HIF-1α is an important regulator of IL-8 expression in human bone marrow stromal cells under hypoxic microenvironment.
  3. p53 deficient breast cancer cells reprogram preadipocytes toward tumor-protective immunomodulatory cells.
  4. Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.
  5. ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits.
  6. SERS analysis of cancer cell-secreted purines reveals a unique paracrine crosstalk in MTAP-deficient tumors.
  1. J Biochem. 2023 Dec 15. pii: mvad105. [Epub ahead of print]
    Merlin/NF2 regulates SLC7A11/xCT expression and cell viability under glucose deprivation at high cell density in glioblastoma cells.
    Itsuki Yamaguchi, Hironori Katoh.
      The cystine/glutamate transporter SLC7A11/xCT is highly expressed in many cancer cells and plays an important role in antioxidant activity by supplying cysteine for glutathione synthesis. Under glucose-depleted conditions, however, SLC7A11-mediated cystine uptake causes oxidative stress and cell death called disulfidptosis, a new form of cell death. We previously reported that high cell density (HD) promotes lysosomal degradation of SLC7A11 in glioblastoma cells, allowing them to survive under glucose-depleted conditions. In this study, we found that the neurofibromatosis type 2 gene, Merlin/NF2 is a key regulator of SLC7A11 in glioblastoma cells at HD. Deletion of Merlin increased SLC7A11 protein level and cystine uptake at HD, leading to promotion of cell death under glucose deprivation. Furthermore, HD significantly decreased SLC7A11 mRNA level, which was restored by Merlin deletion. This study suggests that Merlin suppresses glucose deprivation-induced cell death by downregulating SLC7A11 expression in glioblastoma cells at HD.
    Keywords:  amino acid transport; cell death; cell density; glioblastoma; transcriptional regulation
    DOI:  https://doi.org/10.1093/jb/mvad105
  2. Protoplasma. 2023 Dec 23.
    HIF-1α is an important regulator of IL-8 expression in human bone marrow stromal cells under hypoxic microenvironment.
    Qiqi Huang, Ruolan You, Maoqing Tan, Danni Cai, Hong Zou, Shuxia Zhang, Huifang Huang.
      The secretion of IL-8 has been found increasing for different reasons in human bone marrow stromal cells (BMSCs), resulting in poor prognosis in patients with hematologic neoplasms. Hypoxia, a typical feature of numerous hematologic neoplasms microenvironment, often produces hypoxia inducible factor-1α (HIF-1α) which stabilizes and promotes tumor progression. Besides, hypoxic conditions also induce IL-8 production in BMSCs. However, very little is known about the mechanism of increased IL-8 expression in BMSCs caused by hypoxia. In the present study, HIF-1α and IL-8 were found highly expressed in BMSC lines under hypoxic conditions. In addition, the expression and secretion of IL-8 were significantly inhibited by the knockdown of HIF-1α under hypoxic conditions. Furthermore, HIF-1α was found to transcriptionally regulate IL-8 by binding to the region of IL-8 promoter at - 147 to - 140. Collectively, these results demonstrate that IL-8's increase is partly due to the hypoxic microenvironment in hematologic neoplasms, and activation of HIF-1α in BMSCs contributes to the induction and transcriptional regulation of IL-8 expression.
    Keywords:  Bone marrow stromal cells; HIF-1α; Hematologic neoplasms; Hypoxia; IL-8
    DOI:  https://doi.org/10.1007/s00709-023-01920-z
  3. Proc Natl Acad Sci U S A. 2023 Dec 26. 120(52): e2311460120
    p53 deficient breast cancer cells reprogram preadipocytes toward tumor-protective immunomodulatory cells.
    Ori Hassin, Miriam Sernik, Adi Seligman, Felix C E Vogel, Max D Wellenstein, Joachim Smollich, Coral Halperin, Anna Chiara Pirona, Liron Nomi Toledano, Carolina Dehesa Caballero, Lisa Schlicker, Tomer-Meir Salame, Avital Sarusi Portuguez, Yael Aylon, Ruth Scherz-Shouval, Tamar Geiger, Karin E de Visser, Almut Schulze, Moshe Oren.
      The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and breast tumors, undergo transcriptional, metabolic, and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an inflammatory tumor microenvironment, including increased abundance of Ly6C+ and Ly6G+ myeloid cells and elevated expression of the immune checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 deregulation in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 dysfunction may promote cancer. Further elucidation of the interplay between p53 and adipocytes within the tumor microenvironment may suggest effective therapeutic targets for the treatment of breast cancer patients.
    Keywords:  adipocytes; breast cancer; p53; preadipocytes
    DOI:  https://doi.org/10.1073/pnas.2311460120
  4. Int J Mol Sci. 2023 Dec 13. pii: 17423. [Epub ahead of print]24(24):
    Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.
    Alexander Kalinin, Ekaterina Zubkova, Mikhail Menshikov.
      Cellular senescence is a complex process characterized by irreversible cell cycle arrest. Senescent cells accumulate with age, promoting disease development, yet the absence of specific markers hampers the development of selective anti-senescence drugs. The integrated stress response (ISR), an evolutionarily highly conserved signaling network activated in response to stress, globally downregulates protein translation while initiating the translation of specific protein sets including transcription factors. We propose that ISR signaling plays a central role in controlling senescence, given that senescence is considered a form of cellular stress. Exploring the intricate relationship between the ISR pathway and cellular senescence, we emphasize its potential as a regulatory mechanism in senescence and cellular metabolism. The ISR emerges as a master regulator of cellular metabolism during stress, activating autophagy and the mitochondrial unfolded protein response, crucial for maintaining mitochondrial quality and efficiency. Our review comprehensively examines ISR molecular mechanisms, focusing on ATF4-interacting partners, ISR modulators, and their impact on senescence-related conditions. By shedding light on the intricate relationship between ISR and cellular senescence, we aim to inspire future research directions and advance the development of targeted anti-senescence therapies based on ISR modulation.
    Keywords:  ATF4; ISR; Nrf2; SASP; cellular mechanisms; metabolism; senescence; stress response
    DOI:  https://doi.org/10.3390/ijms242417423
  5. Cell Metab. 2023 Dec 08. pii: S1550-4131(23)00421-7. [Epub ahead of print]
    ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits.
    Charandeep Singh, Byungchang Jin, Nirajan Shrestha, Andrew L Markhard, Apekshya Panda, Sarah E Calvo, Amy Deik, Xingxiu Pan, Austin L Zuckerman, Amel Ben Saad, Kathleen E Corey, Julia Sjoquist, Stephanie Osganian, Roya AminiTabrizi, Eugene P Rhee, Hardik Shah, Olga Goldberger, Alan C Mullen, Valentin Cracan, Clary B Clish, Vamsi K Mootha, Russell P Goodman.
      Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and downregulation after bariatric surgery in humans. These findings highlight how a GCKR-reductive stress-ChREBP axis influences multiple human metabolic traits.
    Keywords:  ChREBP; FGF21; GCK; GCKR; MLIXPL; NAD(+); NADH; fatty liver disease; gastric bypass surgery; metabolism; reductive stress; trigylcerides
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.010
  6. Proc Natl Acad Sci U S A. 2023 Dec 26. 120(52): e2311674120
    SERS analysis of cancer cell-secreted purines reveals a unique paracrine crosstalk in MTAP-deficient tumors.
    Pablo S Valera, Javier Plou, Isabel García, Ianire Astobiza, Cristina Viera, Ana M Aransay, José E Martin, Ivan R Sasselli, Arkaitz Carracedo, Luis M Liz-Marzán.
      The tumor microenvironment (TME) is a dynamic pseudoorgan that shapes the development and progression of cancers. It is a complex ecosystem shaped by interactions between tumor and stromal cells. Although the traditional focus has been on the paracrine communication mediated by protein messengers, recent attention has turned to the metabolic secretome in tumors. Metabolic enzymes, together with exchanged substrates and products, have emerged as potential biomarkers and therapeutic targets. However, traditional techniques for profiling secreted metabolites in complex cellular contexts are limited. Surface-enhanced Raman scattering (SERS) has emerged as a promising alternative due to its nontargeted nature and simplicity of operation. Although SERS has demonstrated its potential for detecting metabolites in biological settings, its application in deciphering metabolic interactions within multicellular systems like the TME remains underexplored. In this study, we introduce a SERS-based strategy to investigate the secreted purine metabolites of tumor cells lacking methylthioadenosine phosphorylase (MTAP), a common genetic event associated with poor prognosis in various cancers. Our SERS analysis reveals that MTAP-deficient cancer cells selectively produce methylthioadenosine (MTA), which is taken up and metabolized by fibroblasts. Fibroblasts exposed to MTA exhibit: i) molecular reprogramming compatible with cancer aggressiveness, ii) a significant production of purine derivatives that could be readily recycled by cancer cells, and iii) the capacity to secrete purine derivatives that induce macrophage polarization. Our study supports the potential of SERS for cancer metabolism research and reveals an unprecedented paracrine crosstalk that explains TME reprogramming in MTAP-deleted cancers.
    Keywords:  Raman spectroscopy; biosensors; metabolic signaling; secretome; tumor metabolism
    DOI:  https://doi.org/10.1073/pnas.2311674120
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