RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis

Wu, Lei; Zhang, Xiao; Lu, Zheng; Zhao, Huakan; Yan, Guifang; Zhang, Qi; Zhou, Yu; Lei, Juan; Zhang, Jiangang; Wang, Jingchun; Rong, Xianglu; Jiang, Lu; Peng, Jin; Chen, Qian; Lam, Sin Man; Shui, Guanghou; Miao, Hongming; Li, Yongsheng

doi:10.1158/2326-6066.cir-19-0261

Cited by 132 publications

(71 citation statements)

References 40 publications

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“…For example, lipid metabolism and fatty acid oxidation have been identified as upregulated in TAMs and involved in pro-tumoral polarization, thereby presenting promising therapy targets. TAMs are found to accumulate lipids as an alternative fuel source in vitro and inhibiting this mechanism leads to reduction in tumor growth in vivo [121,122]. Additionally, targeting cholesterol metabolism elicits anti-tumor functions in TAMs and decreases EMT in vivo, improving chemotherapy resistance [123].…”

Section: Future Perspectivesmentioning

confidence: 99%

Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment

Goede

Driessen

Bossche

2020

Biology

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Tumors consist of a wide variety of cells, including immune cells, that affect tumor progression. Macrophages are abundant innate immune cells in the tumor microenvironment (TME) and are crucial in regulating tumorigenicity. Specific metabolic conditions in the TME can alter the phenotype of tumor-associated macrophages (TAMs) in a direction that supports their pro-tumor functions. One of these conditions is the accumulation of metabolites, also known as oncometabolites. Interactions of oncometabolites with TAMs can promote a pro-tumorigenic phenotype, thereby sustaining cancer cell growth and decreasing the chance of eradication. This review focuses on the metabolic cancer-macrophage crosstalk in the TME. We discuss how cancer cell metabolism and oncometabolites affect macrophage phenotype and function, and conversely how macrophage metabolism can impact tumor progression. Lastly, we propose tumor-secreted exosome-mediated metabolic signaling as a potential factor in tumorigenesis. Insight in these processes may contribute to the development of novel cancer therapies.

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Section: Future Perspectivesmentioning

confidence: 99%

Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment

Goede

Driessen

Bossche

2020

Biology

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“…2h). 27 FAO assay using oleate as a substrate further confirmed that PIWIL1 could promote fatty acid metabolism in HCC cells ( Supplementary Fig. S2g).…”

Section: Resultsmentioning

confidence: 63%

“…47 HCC cells may accelerate FAO to maintain the energy homeostasis to counteract stress-induced cancer cell death. 48 Some specific cell types in the tumor stroma of HCC, such as tumor-initiating cells 49 and TAMs, 27 were found to utilize FAO to generate more ATP for the initiation and progression of HCC. Our findings here showed that PIWIL1 drives FAO as a source of ATP generation in differentiated HCC cells, which was responsible for PIWIL1-associated tumor progression.…”

Section: Discussionmentioning

confidence: 99%

PIWIL1 governs the crosstalk of cancer cell metabolism and immunosuppressive microenvironment in hepatocellular carcinoma

Wang

Tan

et al. 2021

Sig Transduct Target Ther

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Altered energy metabolism of cancer cells shapes the immune cell response in the tumor microenvironment that facilitates tumor progression. Herein, we reported the novel of tumor cell-expressed Piwi Like RNA-Mediated Gene Silencing 1 (PIWIL1) in mediating the crosstalk of fatty acid metabolism and immune response of human hepatocellular carcinoma (HCC). PIWIL1 expression in HCC was increased compared to normal hepatic tissues and was positively correlated with the proliferation rate of HCC cell lines. PIWIL1 overexpression accelerated in vitro proliferation and in vivo growth of HCC tumors, while PIWIL1 knockdown showed opposite effects. PIWIL1 increased oxygen consumption and energy production via fatty acid metabolism without altering aerobic glycolysis. Inhibition of fatty acid metabolism abolished PIWIL1-induced HCC proliferation and growth. RNA-seq analysis revealed that immune system regulation might be involved, which was echoed by the experimental observation that PIWIL1-overexpressing HCC cells attracted myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. MDSCs depletion reduced the proliferation and growth of PIWIL1-overexpressing HCC tumors. Complement C3, whose secretion was induced by PIWIL1 in HCC cells, mediates the interaction of HCC cells with MDSCs by activated p38 MAPK signaling in MDSCs, which in turn initiated expression of immunosuppressive cytokine IL10. Neutralizing IL10 secretion reduced the immunosuppressive activity of MDSCs in the microenvironment of PIWIL1-overexpressing HCC. Taken together, our study unraveled the critical role of PIWIL1 in initiating the interaction of cancer cell metabolism and immune cell response in HCC. Tumor cells-expressed PIWIL1 may be a potential target for the development of novel HCC treatment.

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“…RIPK3 reduction provokes an inhibition of caspase1-mediated cleavage of PPAR γ that promotes FAO pathway activation and M2 polarization within the TME. Consistently, RIPK3 overexpression or FAO blockade prevents TAM-induced immunosuppression and impairs HCC tumorigenesis [ 64 ]. These data suggest a time-dependent relation of caspase-1 activation and RIPK3 downregulation to balance lipid storage and degradation according to TAM's energy needs in tumor tissues.…”

Section: Fatty Acid Metabolism In Tamsmentioning

confidence: 95%

The Metabolic Features of Tumor-Associated Macrophages: Opportunities for Immunotherapy?

Mojsilović

Villar

et al. 2021

Analytical Cellular Pathology

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Besides transformed cells, the tumors are composed of various cell types that contribute to undesirable tumor progression. Tumor-associated macrophages (TAMs) are the most abundant innate immune cells in the tumor microenvironment (TME). Within the TME, TAMs exhibit high plasticity and undergo specific functional metabolic alterations according to the availability of tumor tissue oxygen and nutrients, thus further contributing to tumorigenesis and cancer progression. Here, we review the main functional TAM metabolic patterns influenced by TME, including glycolysis, amino acid, and fatty acid metabolism. Moreover, this review discusses antitumor immunotherapies that affect TAM functionality by inducing cell repolarizing and metabolic profiles towards an antitumoral phenotype. Also, new macrophage-based cell therapeutic technologies recently developed using chimeric antigen receptor bioengineering are exposed, which may overcome all solid tumor physical barriers impeding the current adoptive cell therapies and contribute to developing novel cancer immunotherapies.

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RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis

Cited by 132 publications

References 40 publications

Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment

Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment

PIWIL1 governs the crosstalk of cancer cell metabolism and immunosuppressive microenvironment in hepatocellular carcinoma

The Metabolic Features of Tumor-Associated Macrophages: Opportunities for Immunotherapy?

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