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Tumor Cell-Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid β-Oxidation.

ABSTRACT: Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long-term prognosis in these patients. The CD96⁺ cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell-intrinsic CD96 enhances the chemotherapeutic response in a patient-derived tumor xenograft model. Mechanistically, CD96 enhances mitochondrial fatty acid β-oxidation via the CD155-CD96-Src-Stat3-Opa1 pathway, which subsequently promotes chemoresistance in breast cancer stem cells. A previously unknown role is identified for tumor cell-intrinsic CD96 and an attractive target in improving the chemotherapeutic response.

SUBMITTER: Li J

PROVIDER: S-EPMC9982582 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Tumor Cell-Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid β-Oxidation.

Li Jiang J Xia Qidong Q Di Can C Li Chunni C Si Hang H Zhou Boxuan B Yu Shubin S Li Yihong Y Huang Jingying J Lu Yiwen Y Huang Min M Liang Huixin H Liu Xinwei X Zhao Qiyi Q

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20221229 7

Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long-term prognosis in these patients. The CD96<sup>+</sup> cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell-intrinsic CD96 e ...[more]

PMID: 36581470

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Project description:BackgroundThe oxidation of fatty acids in mitochondria plays an important role in energy metabolism and genetic disorders of this pathway may cause metabolic diseases. Enzyme deficiencies can block the metabolism at defined reactions in the mitochondrion and lead to accumulation of specific substrates causing severe clinical manifestations. Ten of the disorders directly affecting mitochondrial fatty acid oxidation have been well-defined, implicating episodic hypoketotic hypoglycemia provoked by catabolic stress, multiple organ failure, muscle weakness, or hypertrophic cardiomyopathy. Additionally, syndromes of severe maternal illness (HELLP syndrome and AFLP) have been associated with pregnancies carrying a fetus affected by fatty acid oxidation deficiencies. However, little is known about fatty acids kinetics, especially during fasting or exercise when the demand for fatty acid oxidation is increased (catabolic stress).ResultsA computational kinetic network of 64 reactions with 91 compounds and 301 parameters was constructed to study dynamic properties of mitochondrial fatty acid beta-oxidation. Various deficiencies of acyl-CoA dehydrogenase were simulated and verified with measured concentrations of indicative metabolites of screened newborns in Middle Europe and South Australia. The simulated accumulation of specific acyl-CoAs according to the investigated enzyme deficiencies are in agreement with experimental data and findings in literature. Investigation of the dynamic properties of the fatty acid beta-oxidation reveals that the formation of acetyl-CoA - substrate for energy production - is highly impaired within the first hours of fasting corresponding to the rapid progress to coma within 1-2 hours. LCAD deficiency exhibits the highest accumulation of fatty acids along with marked increase of these substrates during catabolic stress and the lowest production rate of acetyl-CoA. These findings might confirm gestational loss to be the explanation that no human cases of LCAD deficiency have been described.ConclusionIn summary, this work provides a detailed kinetic model of mitochondrial metabolism with specific focus on fatty acid beta-oxidation to simulate and predict the dynamic response of that metabolic network in the context of human disease. Our findings offer insight into the disease process (e.g. rapid progress to coma) and might confirm new explanations (no human cases of LCAD deficiency), which can hardly be obtained from experimental data alone.

Project description:Background Defects in the renal fatty acid β-oxidation pathway have been implicated in the development of renal fibrosis. Our group has developed a therapeutic vaccine targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), named PCSK9Qβ-003. In this study, we investigated the potential effectiveness of the PCSK9Qβ-003 vaccine on hypercholesterolemia with renal fibrosis. Methods and Results The low-density lipoprotein receptor+/- male mice fed with a high-cholesterol (1%) Western diet were randomly assigned into 4 groups: the sham group (or the control group), the phosphate-buffered saline group, the Qβ virus-like particles group and the PCSK9Qβ-003 vaccine group. Mice of the PCSK9Qβ-003 group were injected with the PCSK9Qβ-003 vaccine (100 μg/time) every 2 or 4 weeks. The mice were administered with either unilateral ureteral obstruction for 2 weeks or N-nitro-l-arginine methyl ester (50 mg/kg per day) for 6 weeks to establish a renal fibrosis model. Compared with the other 3 groups, the PCSK9Qβ-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in low-density lipoprotein receptor+/- mice with hypercholesterolemia. Compared with the phosphate-buffered saline and Qβ virus-like particles groups, the PCSK9Qβ-003 vaccine improved hepatic steatosis and renal function. Histology analysis showed that the PCSK9Qβ-003 vaccine significantly ameliorated renal lipid accumulation and renal fibrosis. Moreover, the PCSK9Qβ-003 vaccine obviously upregulated the expression of low-density lipoprotein receptor, very-low-density lipoprotein receptor, sterol-regulatory element binding protein 2, and fatty acid β-oxidation-related factors, and ameliorated renal fibrosis-related molecules both in the unilateral ureteral obstruction and N-nitro-l-arginine methyl ester models. Conclusions This study suggested that the PCSK9Qβ-003 vaccine improved renal lipid accumulation and renal fibrosis by regulating fatty acid β-oxidation, which may provide a promising method for treating hypercholesterolemia with renal fibrosis.

Dataset Information

Tumor Cell-Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid β-Oxidation.

Publications

Tumor Cell-Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid β-Oxidation.

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