bims-stacyt 2024-02-18 papers

Proc Natl Acad Sci U S A. 2024 Feb 20. 121(8): e2317343121

Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.

Evan K Noch, Laura Palma, Isaiah Yim, Nayah Bullen, Daniel Barnett, Alexander Walsh, Bhavneet Bhinder, Elisa Benedetti, Jan Krumsiek, Justin Gurvitch, Sumaiyah Khwaja, Daphne Atlas, Olivier Elemento, Lewis C Cantley.

Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.

Keywords: cysteine; glioblastoma; hydrogen peroxide; mitochondrial metabolism; reductive stress

DOI: https://doi.org/10.1073/pnas.2317343121

Sci Adv. 2024 Feb 16. 10(7): eadi1736

Cooperative pro-tumorigenic adaptation to oncogenic RAS through epithelial-to-mesenchymal plasticity.

Hadrien De Blander, Laurie Tonon, Frédérique Fauvet, Roxane M Pommier, Christelle Lamblot, Rahma Benhassoun, Francesca Angileri, Benjamin Gibert, Raphaël Rodriguez, Maria Ouzounova, Anne-Pierre Morel, Alain Puisieux.

In breast cancers, aberrant activation of the RAS/MAPK pathway is strongly associated with mesenchymal features and stemness traits, suggesting an interplay between this mitogenic signaling pathway and epithelial-to-mesenchymal plasticity (EMP). By using inducible models of human mammary epithelial cells, we demonstrate herein that the oncogenic activation of RAS promotes ZEB1-dependent EMP, which is necessary for malignant transformation. Notably, EMP is triggered by the secretion of pro-inflammatory cytokines from neighboring RAS-activated senescent cells, with a prominent role for IL-6 and IL-1α. Our data contrast with the common view of cellular senescence as a tumor-suppressive mechanism and EMP as a process promoting late stages of tumor progression in response to signals from the tumor microenvironment. We highlighted here a pro-tumorigenic cooperation of RAS-activated mammary epithelial cells, which leverages on oncogene-induced senescence and EMP to trigger cellular reprogramming and malignant transformation.

DOI: https://doi.org/10.1126/sciadv.adi1736

CNS Neurosci Ther. 2024 Feb;30(2): e14600

GDF15 is a dynamic biomarker of the integrated stress response in the central nervous system.

Jyoti Asundi, Chunlian Zhang, Diana Donnelly-Roberts, Josè Zavala Solorio, Malleswari Challagundla, Caitlin Connelly, Christina Boch, Jun Chen, Mario Richter, Mohammad Mehdi Maneshi, Andrew M Swensen, Lauren Lebon, Raphael Schiffmann, Subhabrata Sanyal, Carmela Sidrauski, Ganesh Kolumam, Amos Baruch.

AIM: Characterize Growth Differentiation Factor 15 (GDF15) as a secreted biomarker of the integrated stress response (ISR) within the central nervous system (CNS).METHODS: We determined GDF15 levels utilizing in vitro and in vivo neuronal systems wherein the ISR was activated. Primarily, we used the murine model of vanishing white matter disease (VWMD), a neurological disease driven by persistent ISR in the CNS, to establish a link between levels of GDF15 in the cerebrospinal fluid (CSF) and ISR gene expression signature in the CNS. GDF15 was also determined in the CSF of VWM patients.
RESULTS: GDF15 expression was increased concomitant to ISR activation in stress-induced primary astrocytes as well as in retinal ganglion cells following optic nerve crush, while treatment with 2Bact, a specific eIF2B activator, suppressed both the ISR and GDF15. In the VWMD model, CSF GDF15 levels corresponded with the magnitude of the ISR and were reduced by 2BAct. In VWM patients, mean CSF GDF15 was elevated >20-fold as compared to healthy controls, whereas plasma GDF15 was undifferentiated.
CONCLUSIONS: These data suggest that CSF GDF15 is a dynamic marker of ISR activation in the CNS and may serve as a pharmacodynamic biomarker for ISR-modulating therapies.

Keywords: CNS; GDF15; ISR; biomarker

DOI: https://doi.org/10.1111/cns.14600

Cell Oncol (Dordr). 2024 Feb 12.

O-GlcNAcylation of TRIM29 and OGT translation forms a feedback loop to promote adaptive response of PDAC cells to glucose deficiency.

Fu-Ying Zhao, Xue Chen, Jia-Mei Wang, Ye Yuan, Chao Li, Jia Sun, Hua-Qin Wang.

PURPOSE: Glucose not only provides energy for tumor cells, but also provides various biomolecules that are essential for their survival, proliferation and invasion. Therefore, it is of great clinical significance to understand the mechanism of how tumor cells adapt to metabolic stress and maintain their survival. The aim of this research was to study the critical role of OGT and TRIM29 O-GlcNAc modification driven adaptability of PDAC cells to low glucose stress, which might have important medical implications for PDAC therapy.METHODS: Western blotting, mass spectrometry and WGA-immunoprecipitation were used to examined the levels of OGT and O-GlcNAc glycosylated proteins in BxPC3 and SW1990 cells in normal culture and under glucose deprivation conditions. Crystal violet assay, flow cytometry, RIP, RT-qPCR, protein stability assay, biotin pull down were used to investigate the mechanism of OGT and TRIM29-mediated adaptive response to glucose deficiency in PDAC cells.
RESULTS: The current study found that under the condition of low glucose culture, the levels of OGT and O-GlcNAc glycosylation in PDAC cells were significantly higher than those in normal culture. Moreover, the high expression of OGT has a protective effect on PDAC cells under low glucose stress. This study confirmed that there was no significant change in mRNA level and protein degradation of OGT under low glucose stress, which was mainly reflected in the increase of protein synthesis. In addition, O-GlcNAc modification at T120 site plays a critical role in the metabolic adaptive responses mediated by TRIM29.
CONCLUSIONS: Taken together, our study indicated that O-GlcNAcylation of TRIM29 at T120 site and OGT translation forms a loop feedback to facilitate survival of PDAC under glucose deficiency.

Keywords: Low glucose stress; O-GlcNAcylation; PDAC; TRIM29

DOI: https://doi.org/10.1007/s13402-023-00915-5

Front Oncol. 2024 ;14 1331355

Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours.

Kamilla Ja Bigos, Conrado G Quiles, Sapna Lunj, Danielle J Smith, Mechthild Krause, Esther Gc Troost, Catharine M West, Peter Hoskin, Ananya Choudhury.

Hypoxia is a common feature of solid tumours affecting their biology and response to therapy. One of the main transcription factors activated by hypoxia is hypoxia-inducible factor (HIF), which regulates the expression of genes involved in various aspects of tumourigenesis including proliferative capacity, angiogenesis, immune evasion, metabolic reprogramming, extracellular matrix (ECM) remodelling, and cell migration. This can negatively impact patient outcomes by inducing therapeutic resistance. The importance of hypoxia is clearly demonstrated by continued research into finding clinically relevant hypoxia biomarkers, and hypoxia-targeting therapies. One of the problems is the lack of clinically applicable methods of hypoxia detection, and lack of standardisation. Additionally, a lot of the methods of detecting hypoxia do not take into consideration the complexity of the hypoxic tumour microenvironment (TME). Therefore, this needs further elucidation as approximately 50% of solid tumours are hypoxic. The ECM is important component of the hypoxic TME, and is developed by both cancer associated fibroblasts (CAFs) and tumour cells. However, it is important to distinguish the different roles to develop both biomarkers and novel compounds. Fibronectin (FN), collagen (COL) and hyaluronic acid (HA) are important components of the ECM that create ECM fibres. These fibres are crosslinked by specific enzymes including lysyl oxidase (LOX) which regulates the stiffness of tumours and induces fibrosis. This is partially regulated by HIFs. The review highlights the importance of understanding the role of matrix stiffness in different solid tumours as current data shows contradictory results on the impact on therapeutic resistance. The review also indicates that further research is needed into identifying different CAF subtypes and their exact roles; with some showing pro-tumorigenic capacity and others having anti-tumorigenic roles. This has made it difficult to fully elucidate the role of CAFs within the TME. However, it is clear that this is an important area of research that requires unravelling as current strategies to target CAFs have resulted in worsened prognosis. The role of immune cells within the tumour microenvironment is also discussed as hypoxia has been associated with modulating immune cells to create an anti-tumorigenic environment. Which has led to the development of immunotherapies including PD-L1. These hypoxia-induced changes can confer resistance to conventional therapies, such as chemotherapy, radiotherapy, and immunotherapy. This review summarizes the current knowledge on the impact of hypoxia on the TME and its implications for therapy resistance. It also discusses the potential of hypoxia biomarkers as prognostic and predictive indictors of treatment response, as well as the challenges and opportunities of targeting hypoxia in clinical trials.

Keywords: cancer associated fibroblasts; extracellular matrix; hypoxia; immune cells; tumour microenvironment

DOI: https://doi.org/10.3389/fonc.2024.1331355

FEBS J. 2024 Feb 13.

Mitochondrial dysfunction and cisplatin sensitivity in gastric cancer: GDF15 as a master player.

Maria Cavinato.

Gastric cancer, a major global health concern, poses challenges in effective treatment, notably due to chemoresistance. This study investigates the role of growth/differentiation factor-15 (GDF-15) in mitochondrial dysfunction and its impact on cisplatin sensitivity in gastric cancer cells. In this issue of The FEBS Journal, Wang et al. demonstrate that GDF15 upregulation is associated with cisplatin insensitivity, mediated by the ATF4-CHOP pathway and reactive oxygen species-activated general control nonderepressible 2 [Wang S-F et al. (2023) FEBS J, https://doi.org/10.1111/febs.16992]. Connecting these insights, we explore the broader implications of GDF15 expression in the aging-cancer axis, particularly its involvement in cellular senescence and the senescence-associated secretory phenotype (SASP). This study suggests that GDF15 released by senescent cells could contribute to tumor progression, indicating potential avenues for therapeutic intervention by targeting senescent cells and their SASP. While the study provides valuable insights into mitigating cisplatin resistance, further research is crucial to fully understand the role of GDF15 in the tumor microenvironment and its potential feedback loops promoting tumorigenesis.

Keywords: GDF15; cancer; cisplatin resistance; senescence

DOI: https://doi.org/10.1111/febs.17087