bims-stacyt 2023-08-27 papers

Pharmacol Ther. 2023 Aug 23. pii: S0163-7258(23)00183-3. [Epub ahead of print] 108519

Lactate acidosis and simultaneous recruitment of TGF-β leads to alter plasticity of hypoxic cancer cells in tumor microenvironment.

Saumya Rastogi, Shashank Shekher Mishra, Mandeep Kumar Arora, Gaurav Kaithwas, Sugato Banerjee, Velayutham Ravichandiran, Subhadeep Roy, Lakhveer Singh.

Lactate acidosis is often observed in the tumor microenvironment (TME) of solid tumors. This is because glucose breaks down quickly via glycolysis, causing lactate acidity. Lactate is harmful to healthy cells, but is a major oncometabolite for solid cancer cells that do not receive sufficient oxygen. As an oncometabolite, it helps tumor cells perform different functions, which helps solid hypoxic tumor cells spread to other parts of the body. Studies have shown that the acidic TME contains VEGF, Matrix metalloproteinases (MMPs), cathepsins, and transforming growth factor-β (TGF-β), all of which help spread in direct and indirect ways. Although each cytokine is important in its own manner in the TME, TGF-β has received much attention for its role in metastatic transformation. Several studies have shown that lactate acidosis can cause TGF-β expression in solid hypoxic cancers. TGF-β has also been reported to increase the production of fatty acids, making cells more resistant to treatment. TGF-β has also been shown to control the expression of VEGF and MMPs, which helps solid hypoxic tumors become more aggressive by helping them spread and create new blood vessels through an unknown process. The role of TGF-β under physiological conditions has been described previously. In this study, we examined the role of TGF-β, which is induced by lactate acidosis, in the spread of solid hypoxic cancer cells. We also found that TGF-β and lactate work together to boost fatty acid production, which helps angiogenesis and invasiveness.

Keywords: Angiogenesis; Fatty acid synthesis; Hypoxia; Invasiveness; Transforming growth factor (TGF-β)

DOI: https://doi.org/10.1016/j.pharmthera.2023.108519

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

bioRxiv. 2023 Apr 12. pii: 2023.04.12.536613. [Epub ahead of print]

Senescence-specific translation dysregulation desensitizes cells to stress by inhibiting activation of the integrated stress response.

Matthew J Payea, Showkat A Dar, Carlos Anerillas, Jennifer L Martindale, Cedric Belair, Rachel Munk, Sulochan Malla, Jinshui Fan, Yulan Piao, Xiaoling Yang, Abid Rehman, Nirad Banskota, Kotb Abdelmohsen, Myriam Gorospe, Manolis Maragkakis.

Senescence is a state of indefinite cell cycle arrest associated with aging, cancer, and age-related diseases. Here, using label-based mass spectrometry, ribosome profiling and nanopore direct RNA sequencing, we explore the coordinated interaction of translational and transcriptional programs of human cellular senescence. We find that translational deregulation and a corresponding maladaptive integrated stress response (ISR) is a hallmark of senescence that desensitizes senescent cells to stress. We show that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress the stress response transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames. Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. Furthermore, absent a response, stress exacerbates the senescence secretory phenotype and inflammatory pathways thus acting as a possible mechanistic link to disease. Our results reveal a novel mechanism that senescent cells exploit to evade an adaptive stress response and remain viable.

DOI: https://doi.org/10.1101/2023.04.12.536613

Nat Commun. 2023 Aug 24. 14(1): 5179

Cancer-cell-secreted miR-204-5p induces leptin signalling pathway in white adipose tissue to promote cancer-associated cachexia.

Yong Hu, Liu Liu, Yong Chen, Xiaohui Zhang, Haifeng Zhou, Sheng Hu, Xu Li, Meixin Li, Juanjuan Li, Siyuan Cheng, Yong Liu, Yancheng Xu, Wei Yan.

Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia.

DOI: https://doi.org/10.1038/s41467-023-40571-9