bims-stacyt 2024-12-08 papers

Nat Commun. 2024 Dec 03. 15(1): 10539

Tumor-derived miR-9-5p-loaded EVs regulate cholesterol homeostasis to promote breast cancer liver metastasis in mice.

Mei-Xin Li, Sheng Hu, He-Hua Lei, Meng Yuan, Xu Li, Wen-Kui Hou, Xiang-Jie Huang, Bing-Wen Xiao, Teng-Xiang Yu, Xiao-Hui Zhang, Xiao-Ting Wu, Wen-Qiang Jing, Hyeon-Jeong Lee, Juan-Juan Li, Da Fu, Li-Min Zhang, Wei Yan.

Cancer cells secrete extracellular vesicles (EV) encapsulating bioactive cargoes to facilitate inter-organ communication in vivo and are emerging as critical mediators of tumor progression and metastasis, a condition which is often accompanied by a dysregulated cholesterol metabolism. Whether EVs are involved in the control of cholesterol homeostasis during tumor metastasis is still undefined and warrant further investigation. Here, we find that breast cancer-derived exosomal miR-9-5p induces the expression of HMGCR and CH25H, two enzymes involved in cholesterol synthesis and the conversion of 25-hydroxycholesterol from cholesterol by targeting INSIG1, INSIG2 and ATF3 genes in the liver. Notably, in vivo miR-9-5p antagomir treatment and genetic CH25H ablation prevents tumor metastasis in a mouse model of breast cancer. Thus, our findings reveal the regulatory mechanism of tumor-derived miR-9-5p in liver metastasis by linking oxysterol metabolism and Kupffer cell polarization, shedding light on future applications for cancer diagnosis and treatment.

DOI: https://doi.org/10.1038/s41467-024-54706-z

Mol Cancer Res. 2024 Dec 06.

Stress and obesity signaling converge on CREB phosphorylation to promote pancreatic cancer.

Xiaoying Sun, Yaroslav Teper, James Sinnet-Smith, Mineh Markarian, O Joe Hines, Gang Li, Guido Eibl, Enrique Rozengurt.

One of the deadliest types of cancer is pancreatic ductal adenocarcinoma (PDAC). Chronic stress and obesity are recognized as risk factors for PDAC. We hypothesized that the combination of stress and obesity strongly promotes pancreatic cancer development and growth. Here, we show that the stress mediator norepinephrine and the beta adrenergic receptor agonist isoproterenol rapidly stimulate CREB phosphorylation at Ser133 in human PDAC cells. Exposure to the non-selective beta adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551 blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. Stimulation of PDAC cells with neurotensin, a neuropeptide implicated in obesity and PDAC, also stimulated CREB phosphorylation at Ser133. Mechanistically, norepinephrine induced CREB phosphorylation at Ser133 via PKA whereas neurotensin promoted CREB phosphorylation predominantly through protein kinase D (PKD). Our results indicate that CREB is a point of signal convergence that mediates proliferation in PDAC cells and raised the possibility that stress and diet cooperate in promoting PDAC in vivo. To test this notion, mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, calorie diet (HFCD) that promotes early PDAC development were subjected to social isolation stress (SIS). We show that SIS induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in KC mice subjected to an obesogenic HFCD. Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer.

DOI: https://doi.org/10.1158/1541-7786.MCR-24-0785

Angiogenesis. 2024 Dec 05. 28(1): 4

Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) drives abnormal pericyte-rich vasculature in triple-negative breast cancer.

Marianna Moro, Federica Carolina Balestrero, Giorgia Colombo, Simone Torretta, Nausicaa Clemente, Valerio Ciccone, Erika Del Grosso, Sandra Donnini, Cristina Travelli, Fabrizio Condorelli, Sabina Sangaletti, Armando A Genazzani, Ambra A Grolla.

Tumour angiogenesis supports malignant cells with oxygen and nutrients to promote invasion and metastasis. A number of cytokines released in situ participate in the recruitment of endothelial cells and pericytes to trigger the formation of novel blood vessels, which are often abnormal, leaky, and disorganized. Nicotinamide phosphoribosyltransferase is a key intracellular enzyme involved in NAD metabolism and is up regulated in many cancers to meet bioenergetic demands. Yet, the same protein is also secreted extracellularly (eNAMPT), where it acts as a pro-inflammatory cytokine. High plasma eNAMPT levels have been reported in breast cancer patients and correlate with aggressiveness and prognosis. We now report that in a triple-negative breast cancer model, enriching the tumour microenvironment with eNAMPT leads to abundant angiogenesis and increased metastatization. Atypically, the eNAMPT-mediated pro-angiogenic effect is mainly directed to NG2+ pericytes. Indeed, eNAMPT acts as chemoattractant for pericytes and coordinates vessel-like tube formation, in synergism with the classical factor PDGF-BB. Stimulation of pericytes by eNAMPT leads to a pro-inflammatory activation, characterized by the overexpression of key chemokines (CXCL8, CXCL1, CCL2) and VCAM1, via NF-κB signalling. All these effects were ablated by the use of C269, an anti-eNAMPT neutralizing antibody, suggesting that this might represent a novel anti-angiogenic pharmacological approach for triple-negative breast cancer.

Keywords: Angiogenesis; Breast cancer; Cytokines; Pericytes; Tumour microenvironment

DOI: https://doi.org/10.1007/s10456-024-09956-2

Sci Signal. 2024 Dec 03. 17(865): eadk7971

ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress.

Xu Xu, Arturo Mendoza, Christopher S Krumm, Shi Su, Mariana Acuña, Curtis J Bare, Corey D Holman, Marissa Cortopassi, Hayley T Nicholls, Vincent Dartigue, Anthony N Hollenberg, Ann-Hwee Lee, Susan J Hagen, David E Cohen.

Activation of thermogenic brown adipose tissue (BAT) and inducible beige adipose tissue (BeAT) is triggered by environmental or metabolic stimuli, including cold ambient temperatures and nutrient stress. Thioesterase superfamily member 1 (Them1), a long-chain fatty acyl-CoA thioesterase that is enriched in BAT, suppresses acute cold-induced thermogenesis. Here, we demonstrate that Them1 expression was induced in BAT and BeAT by the carbohydrate response element binding protein (ChREBP) in response to chronic cold exposure or to the activation of the integrated stress response (ISR) by nutrient excess. Under either condition, Them1 suppressed energy expenditure. Consequently, mice lacking Them1 in BAT and BeAT exhibited resistance to obesity and glucose intolerance induced by feeding with a high-fat diet. During chronic cold exposure or ISR activation, Them1 accumulated in the nucleus, where it interacted with ChREBP and reduced the expression of its target genes, including those encoding enzymes that mediate glycolysis and de novo lipogenesis. These findings demonstrate that in response to chronic cold- or nutrient-induced stress, the induction of Them1 by ChREBP limits thermogenesis while coordinately reducing glucose utilization and lipid biosynthesis through its distinct cytoplasmic and nuclear activities. Targeted inhibition of Them1 could be a potential therapeutic approach to increase the activity of BAT and BeAT to enhance energy expenditure in the management of obesity-associated metabolic disorders.

DOI: https://doi.org/10.1126/scisignal.adk7971

Nature. 2024 Dec 04.

Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.

Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.

DOI: https://doi.org/10.1038/s41586-024-08285-0