Status
Public on May 04, 2023
Title
ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer [scRNA-Seq]
Experiment type
Expression profiling by high throughput sequencing
Summary
Acetate metabolism is an important metabolic pathway in many types of cancers and is primarily controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. However, the consequences of inhibiting tumor acetate metabolism on the tumor microenvironment and anti-tumor immunity are unknown. Herein we demonstrate that the growth of ACSS2 deficient triple negative breast cancer is severely impaired when host immunity is intact and, in many instances, ACSS2 deficient tumors are fully cleared by the immune system. Pharmacological inhibition of ACSS2 using a potent small molecule inhibitor reproduces these effects and enhances the efficacy of standard of care chemotherapy for TNBC. Single cell RNA sequencing of vehicle versus ACSS2 inhibitor treated tumors indicates differentiation and activation of T cells suggesting a crosstalk between acetate metabolism and immune cells in the tumor microenvironment. Our data suggest that blocking ACSS2 and acetate metabolism in tumors increases the availability of acetate in the tumor microenvironment. Tumor infiltrating T cells can then use acetate as a fuel source due to the relatively high expression of acetyl-CoA synthetase 1 (ACSS1), which is impervious to ACSS2 inhibitors. In this manner, ACSS1-driven oxidation of acetate in T cells helps to metabolically bolster anti-tumor immune responses. Based on our findings, we propose a completely novel paradigm for ACSS2 inhibitors as metaboimmunomodulators that dually act as inhibitors of tumor cell metabolism and modulators of tumor immunity.
Overall design
RNA-seq of different Bmal1 status
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Submission date
May 05, 2022
Last update date
May 04, 2023
Contact name
Priyankara J Wickramasinghe
Phone
2154956837
Organization name
The Wistar Institute
Department
Bioinformatics
Lab
Genomics
Street address
3601 Spruce Street
City
Philadelphia
State/province
PA
ZIP/Postal code
19104
Country
USA
Samples (2)
GSM6107662
Pool of 3 vehicle and 3 ACSS2i treated samples (GE)
GSM6107663
Pool of 3 vehicle and 3 ACSS2i treated samples (protein)
This SubSeries is part of SuperSeries:
GSE202281
ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer
Relations
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Format
Supplementary file
Size
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File type/resource
GSE202280_pool_barcodes.tsv.gz
48.4 Kb
(ftp) (http)
TSV
GSE202280_pool_features.tsv.gz
272.9 Kb
(ftp) (http)
TSV
GSE202280_samples_564_names.xlsx
11.0 Kb
(ftp) (http)
XLSX
Raw data are available in SRA
Processed data are available on Series record