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Tumor Cell-Intrinsic NIK Shapes Metabolic Crosstalk Between Tumors and Brown Adipose Tissue
Published:
04 September 2025
by MDPI
in The 1st International Online Conference on Diseases
session Endocrine and Metabolic Disorders
Abstract:
- Introduction and Objective: Cancer cachexia pivotally influences morbidity and mortality. Brown adipose tissue (BAT) is aberrantly activated by tumor-derived factors, contributing to weight loss and cachexia. NF-κB-inducing kinase (NIK) is highly activated in cancer cells, prompting us to decipher the role of NIK in tumor-stimulation of BAT.
- Methods: NIK was overexpressed (NIK-Tg) or deleted (NIK-KO) specifically in bile duct epithelial cells. NIK-Tg, NIK-KO, and wild-type (WT) control mice were treated with thioacetamine (TAA) to induce intrahepatic cholangiocarcinoma (iCCA). NIK was deleted via CRISPR/Cas9 in HuCCT1 cells (HuCCT1-KO), a human iCCA line. Conditioned medium was prepared from huCCT1-KO and HuCCT1 cells and used to stimulate brown adipocyte culture. HuCCT1-KO and TuCCT1 cells were injected subcutaneously into immunodeficient mice, and tumor growth and BAT activation were assessed.
- Results: TAA promoted iCCA to a dramatically higher degree in NIK-Tg than in WT mice; conversely, NIK-KO mice were resistant to TAA-induced iCCA. Likewise, ablation of NIK also markedly suppressed tumor growth from HuCCT1-KO cells relative to tumors from HuCCT1 cells. BAT expression of UCP1 and other thermogenic genes was tremendously higher in tumor-bearing NIK-Tg mice relative to iCCA-free WT mice. Consistently, BAT was activated to a markedly higher level in mice transplanted with HuCCT1 cells (large tumors) relative to mice transplanted with HuCCT1-KO cells (small tumors). HuCCT1-KO conditioned medium activated the thermogenic program in brown adipocyte culture to a substantially higher level than HuCCT1 conditioned medium.
- Conclusion: Aberrant activation of biliary NIK increases liver cancer risk. NIK is required for production and secretion of soluble tumor mediators that stimulate BAT and cancer cachexia. NIK inhibitors may serve as a potential medication for the treatment of cancer and cancer cachexia.
Keywords: Cancer; NIK; Adipose tissue; Crosstalk
