bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023‒11‒26
two papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Unravelling the Role of Cancer Cell-Derived Extracellular Vesicles in Muscle Atrophy, Lipolysis, and Cancer-Associated Cachexia.
  2. A PERK-Specific Inhibitor Blocks Metastatic Progression by Limiting Integrated Stress Response-Dependent Survival of Quiescent Cancer Cells.
  1. Cells. 2023 Nov 09. pii: 2598. [Epub ahead of print]12(22):
    Unravelling the Role of Cancer Cell-Derived Extracellular Vesicles in Muscle Atrophy, Lipolysis, and Cancer-Associated Cachexia.
    Akbar L Marzan, Sai V Chitti.
      Cancer-associated cachexia is a metabolic syndrome that causes significant reduction in whole-body weight due to excessive loss of muscle mass accompanied by loss of fat mass. Reduced food intake and several metabolic abnormalities, such as increased energy expenditure, excessive catabolism, and inflammation, are known to drive cachexia. It is well documented that cancer cells secrete EVs in abundance which can be easily taken up by the recipient cell. The cargo biomolecules carried by the EVs have the potential to alter the signalling pathways and function of the recipient cells. EV cargo includes proteins, nucleic acids, lipids, and metabolites. Tumour-secreted EVs have been found to alter the metabolic and biological functions of adipose and muscle tissue, which aids in the development of the cachexia phenotype. To date, no medical intervention or FDA-approved drug exists that can completely reverse cachexia. Therefore, understanding how cancer-derived EVs contribute to the onset and progression of cancer-associated cachexia may help with the identification of new biomarkers as well as provide access to novel treatment alternatives. The goal of this review article is to discuss the most recent research on cancer-derived EVs and their function in cellular crosstalk that promotes catabolism in muscle and adipose tissue during cancer-induced cachexia.
    Keywords:  browning; cancer-associated cachexia; extracellular vesicles; lipolysis; muscle atrophy
    DOI:  https://doi.org/10.3390/cells12222598
  2. Clin Cancer Res. 2023 Nov 20. OF1-OF18
    A PERK-Specific Inhibitor Blocks Metastatic Progression by Limiting Integrated Stress Response-Dependent Survival of Quiescent Cancer Cells.
    Veronica Calvo, Wei Zheng, Anna Adam-Artigues, Kirk A Staschke, Xin Huang, Julie F Cheung, Ana Rita Nobre, Sho Fujisawa, David Liu, Maria Fumagalli, David Surguladze, Michael E Stokes, Ari Nowacek, Mark Mulvihill, Eduardo F Farias, Julio A Aguirre-Ghiso.
      PURPOSE: The integrated stress response (ISR) kinase PERK serves as a survival factor for both proliferative and dormant cancer cells. We aim to validate PERK inhibition as a new strategy to specifically eliminate solitary disseminated cancer cells (DCC) in secondary sites that eventually reawake and originate metastasis.EXPERIMENTAL DESIGN: A novel clinical-grade PERK inhibitor (HC4) was tested in mouse syngeneic and PDX models that present quiescent/dormant DCCs or growth-arrested cancer cells in micro-metastatic lesions that upregulate ISR.
    RESULTS: HC4 significantly blocks metastasis, by killing quiescent/slow-cycling ISRhigh, but not proliferative ISRlow DCCs. HC4 blocked expansion of established micro-metastasis that contained ISRhigh slow-cycling cells. Single-cell gene expression profiling and imaging revealed that a significant proportion of solitary DCCs in lungs were indeed dormant and displayed an unresolved ER stress as revealed by high expression of a PERK-regulated signature. In human breast cancer metastasis biopsies, GADD34 expression (PERK-regulated gene) and quiescence were positively correlated. HC4 effectively eradicated dormant bone marrow DCCs, which usually persist after rounds of therapies. Importantly, treatment with CDK4/6 inhibitors (to force a quiescent state) followed by HC4 further reduced metastatic burden. In HNSCC and HER2+ cancers HC4 caused cell death in dormant DCCs. In HER2+ tumors, PERK inhibition caused killing by reducing HER2 activity because of sub-optimal HER2 trafficking and phosphorylation in response to EGF.
    CONCLUSIONS: Our data identify PERK as a unique vulnerability in quiescent or slow-cycling ISRhigh DCCs. The use of PERK inhibitors may allow targeting of pre-existing or therapy-induced growth arrested "persister" cells that escape anti-proliferative therapies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-1427
This page is being maintained by Thomas Krichel. It was last updated on 2024‒01‒06 at 17:43.