bims-stacyt 2024-05-26 papers

Gastroenterology. 2024 May 18. pii: S0016-5085(24)04931-X. [Epub ahead of print]

The integrated stress response in pancreatic development, tissue homeostasis, and cancer.

Greg Malnassy, Leah Ziolkowski, Kay F Macleod, Scott A Oakes.

Present in all eukaryotic cells, the integrated stress response (ISR) is a highly coordinated signaling network that controls cellular behavior, metabolism and survival in response to diverse stresses. The ISR is initiated when any one of four stress sensing kinases (PERK, GCN2, PKR, HRI) becomes activated to phosphorylate the protein translation initiation factor eIF2α, shifting gene expression toward a comprehensive rewiring of cellular machinery to promote adaptation. While the ISR has been shown to play an important role in the homeostasis of multiple tissues, evidence suggests that it is particularly crucial for the development and ongoing health of the pancreas. Among the most synthetically dynamic tissues in the body, the exocrine and endocrine pancreas relies heavily on the ISR to rapidly adjust cell function to meet the metabolic demands of the organism. The hardwiring of the ISR into normal pancreatic functions and adaptation to stress may explain why it is a commonly utilized pro-oncogenic and therapy-resistance mechanism in both pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PanNETs). Here we review what is known about the key roles that the ISR plays in the development, homeostasis, and neoplasia of the pancreas.

Keywords: diabetes; pancreatic ductal adenocarcinoma; pancreatic neuroendocrine tumors; pancreatitis

DOI: https://doi.org/10.1053/j.gastro.2024.05.009

Elife. 2024 May 24. pii: RP95652. [Epub ahead of print]13

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer-driven tissue factors in shaping nutrient availability in these tumors.

Keywords: cancer; cancer biology; human; metabolism; tumor microenvironment

DOI: https://doi.org/10.7554/eLife.95652

Cell Death Differ. 2024 May 18.

m6A demethylation of FOSL1 mRNA protects hepatoma cells against necrosis under glucose deprivation.

Chun-Rui Wang, Jun-Hua Gong, Zhi-Bo Zhao, Qian Zhu, Bian Shu, Jie-Jun Hu, Dong Cai, Xin-Yi Liu, Xin Dai, Chan Qiu, Jian-Ping Gong, Guo-Chao Zhong.

Stress-adaptive mechanisms enabling cancer cells to survive under glucose deprivation remain elusive. N6-methyladenosine (m6A) modification plays important roles in determining cancer cell fate and cellular stress response to nutrient deficiency. However, whether m6A modification functions in the regulation of cancer cell survival under glucose deprivation is unknown. Here, we found that glucose deprivation reduced m6A modification levels. Increasing m6A modification resulted in increased hepatoma cell necrosis under glucose deprivation, whereas decreasing m6A modification had an opposite effect. Integrated m6A-seq and RNA-seq revealed potential targets of m6A modification under glucose deprivation, including the transcription factor FOSL1; further, glucose deprivation upregulated FOSL1 by inhibiting FOSL1 mRNA decay in an m6A-YTHDF2-dependent manner through reducing m6A modification in its exon1 and 5'-UTR regions. Functionally, FOSL1 protected hepatoma cells against glucose deprivation-induced necrosis in vitro and in vivo. Mechanistically, FOSL1 transcriptionally repressed ATF3 by binding to its promoter. Meanwhile, ATF3 and MAFF interacted via their leucine zipper domains to form a heterodimer, which competed with NRF2 for binding to antioxidant response elements in the promoters of NRF2 target genes, thereby inhibiting their transcription. Consequently, FOSL1 reduced the formation of the ATF3-MAFF heterodimer, thereby enhancing NRF2 transcriptional activity and the antioxidant capacity of glucose-deprived-hepatoma cells. Thus, FOSL1 alleviated the necrosis-inducing effect of glucose deprivation-induced reactive oxygen species accumulation. Collectively, our study uncovers the protective role of m6A-FOSL1-ATF3 axis in hepatoma cell necrosis under glucose deprivation, and may provide new targets for cancer therapy.

DOI: https://doi.org/10.1038/s41418-024-01308-3

Cell Death Discov. 2024 May 18. 10(1): 237

AMPK-a key factor in crosstalk between tumor cell energy metabolism and immune microenvironment?

Na Wang, Bofang Wang, Ewetse Paul Maswikiti, Yang Yu, Kewei Song, Chenhui Ma, Xiaowen Han, Huanhuan Ma, Xiaobo Deng, Rong Yu, Hao Chen.

Immunotherapy has now garnered significant attention as an essential component in cancer therapy during this new era. However, due to immune tolerance, immunosuppressive environment, tumor heterogeneity, immune escape, and other factors, the efficacy of tumor immunotherapy has been limited with its application to very small population size. Energy metabolism not only affects tumor progression but also plays a crucial role in immune escape. Tumor cells are more metabolically active and need more energy and nutrients to maintain their growth, which causes the surrounding immune cells to lack glucose, oxygen, and other nutrients, with the result of decreased immune cell activity and increased immunosuppressive cells. On the other hand, immune cells need to utilize multiple metabolic pathways, for instance, cellular respiration, and oxidative phosphorylation pathways to maintain their activity and normal function. Studies have shown that there is a significant difference in the energy expenditure of immune cells in the resting and activated states. Notably, competitive uptake of glucose is the main cause of impaired T cell function. Conversely, glutamine competition often affects the activation of most immune cells and the transformation of CD4+T cells into inflammatory subtypes. Excessive metabolite lactate often impairs the function of NK cells. Furthermore, the metabolite PGE2 also often inhibits the immune response by inhibiting Th1 differentiation, B cell function, and T cell activation. Additionally, the transformation of tumor-suppressive M1 macrophages into cancer-promoting M2 macrophages is influenced by energy metabolism. Therefore, energy metabolism is a vital factor and component involved in the reconstruction of the tumor immune microenvironment. Noteworthy and vital is that not only does the metabolic program of tumor cells affect the antigen presentation and recognition of immune cells, but also the metabolic program of immune cells affects their own functions, ultimately leading to changes in tumor immune function. Metabolic intervention can not only improve the response of immune cells to tumors, but also increase the immunogenicity of tumors, thereby expanding the population who benefit from immunotherapy. Consequently, identifying metabolic crosstalk molecules that link tumor energy metabolism and immune microenvironment would be a promising anti-tumor immune strategy. AMPK (AMP-activated protein kinase) is a ubiquitous serine/threonine kinase in eukaryotes, serving as the central regulator of metabolic pathways. The sequential activation of AMPK and its associated signaling cascades profoundly impacts the dynamic alterations in tumor cell bioenergetics. By modulating energy metabolism and inflammatory responses, AMPK exerts significant influence on tumor cell development, while also playing a pivotal role in tumor immunotherapy by regulating immune cell activity and function. Furthermore, AMPK-mediated inflammatory response facilitates the recruitment of immune cells to the tumor microenvironment (TIME), thereby impeding tumorigenesis, progression, and metastasis. AMPK, as the link between cell energy homeostasis, tumor bioenergetics, and anti-tumor immunity, will have a significant impact on the treatment and management of oncology patients. That being summarized, the main objective of this review is to pinpoint the efficacy of tumor immunotherapy by regulating the energy metabolism of the tumor immune microenvironment and to provide guidance for the development of new immunotherapy strategies.

DOI: https://doi.org/10.1038/s41420-024-02011-5

Nat Rev Endocrinol. 2024 May 20.

Transcriptional control of metabolism by interferon regulatory factors.

Zunair Ahmad, Wahab Kahloan, Evan D Rosen.

Interferon regulatory factors (IRFs) comprise a family of nine transcription factors in mammals. IRFs exert broad effects on almost all aspects of immunity but are best known for their role in the antiviral response. Over the past two decades, IRFs have been implicated in metabolic physiology and pathophysiology, partly as a result of their known functions in immune cells, but also because of direct actions in adipocytes, hepatocytes, myocytes and neurons. This Review focuses predominantly on IRF3 and IRF4, which have been the subject of the most intense investigation in this area. IRF3 is located in the cytosol and undergoes activation and nuclear translocation in response to various signals, including stimulation of Toll-like receptors, RIG-I-like receptors and the cGAS-STING pathways. IRF3 promotes weight gain, primarily by inhibiting adipose thermogenesis, and also induces inflammation and insulin resistance using both weight-dependent and weight-independent mechanisms. IRF4, meanwhile, is generally pro-thermogenic and anti-inflammatory and has profound effects on lipogenesis and lipolysis. Finally, new data are emerging on the role of other IRF family members in metabolic homeostasis. Taken together, data indicate that IRFs serve as critical yet underappreciated integrators of metabolic and inflammatory stress.

DOI: https://doi.org/10.1038/s41574-024-00990-0