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Mitoribosomal defec...
Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion
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Song, Byong-Sop (author)
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Moon, Ji Sun (author)
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Tian, Jingwen (author)
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Lee, Ho Yeop (author)
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Sim, Byeong Chang (author)
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Kim, Seok-Hwan (author)
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Kang, Seul Gi (author)
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Kim, Jung Tae (author)
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Ha, Thi (author)
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- Benfeitas, Rui (author)
- Stockholms universitet,Science for Life Laboratory (SciLifeLab)
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Kim, Yeongmin (author)
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Park, Sanghee (author)
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Wolfe, Robert R. (author)
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Eun, Hyuk Soo (author)
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Shong, Minho (author)
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Lee, Sunjae (author)
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Kim, Il-Young (author)
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Yi, Hyon-Seung (author)
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(creator_code:org_t)
- 2022-05-17
- 2022
- English.
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In: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 10:5
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
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- Background Mitochondria are involved in cancer energy metabolism, although the mechanisms underlying the involvement of mitoribosomal dysfunction in hepatocellular carcinoma (HCC) remain poorly understood. Here, we investigated the effects of mitoribosomal impairment-mediated alterations on the immunometabolic characteristics of liver cancer.Methods We used a mouse model of HCC, liver tissues from patients with HCC, and datasets from The Cancer Genome Atlas (TCGA) to elucidate the relationship between mitoribosomal proteins (MRPs) and HCC. In a mouse model, we selectively disrupted expression of the mitochondrial ribosomal protein CR6-interacting factor 1 (CRIF1) in hepatocytes to determine the impact of hepatocyte-specific impairment of mitoribosomal function on liver cancer progression. The metabolism and immunophenotype of liver cancer was assessed by glucose flux assays and flow cytometry, respectively.Results Single-cell RNA-seq analysis of tumor tissue and TCGA HCC transcriptome analysis identified mitochondrial defects associated with high-MRP expression and poor survival outcomes. In the mouse model, hepatocyte-specific disruption of the mitochondrial ribosomal protein CRIF1 revealed the impact of mitoribosomal dysfunction on liver cancer progression. Crif1 deficiency promoted programmed cell death protein 1 expression by immune cells in the hepatic tumor microenvironment. A [U-13C6]-glucose tracer demonstrated enhanced glucose entry into the tricarboxylic acid cycle and lactate production in mice with mitoribosomal defects during cancer progression. Mice with hepatic mitoribosomal defects also exhibited enhanced progression of liver cancer accompanied by highly exhausted tumor-infiltrating T cells. Crif1 deficiency induced an environment unfavorable to T cells, leading to exhaustion of T cells via elevation of reactive oxygen species and lactate production.Conclusions Hepatic mitoribosomal defects promote glucose partitioning toward glycolytic flux and lactate synthesis, leading to T cell exhaustion and cancer progression. Overall, the results suggest a distinct role for mitoribosomes in regulating the immunometabolic microenvironment during HCC progression.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- liver neoplasms
- lymphocytes
- tumor-infiltrating
- gene expression profiling
- inflammation
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Song, Byong-Sop
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Moon, Ji Sun
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Tian, Jingwen
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Lee, Ho Yeop
-
Sim, Byeong Chan ...
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Kim, Seok-Hwan
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show more...
-
Kang, Seul Gi
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Kim, Jung Tae
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Ha, Thi
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Benfeitas, Rui
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Kim, Yeongmin
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Park, Sanghee
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Wolfe, Robert R.
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Eun, Hyuk Soo
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Shong, Minho
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Lee, Sunjae
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Kim, Il-Young
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Yi, Hyon-Seung
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Journal for Immu ...
- By the university
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Stockholm University