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ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE202281 | GEO | 2023/05/04

REPOSITORIES: GEO

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ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer [RNA-Seq]

Project description: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.

2023-05-04 | GSE202279 | GEO

ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer [scRNA-Seq]

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ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer

Project description:ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer

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ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer [RNA-Seq]

Project description:ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer [RNA-Seq]

| PRJNA835332 | ENA

ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer [scRNA-Seq]

Project description:ACSS2 inhibitors act as metabo-immunomodulators in triple negative breast cancer [scRNA-Seq]

| PRJNA835331 | ENA

Response and resistance to BET bromodomain inhibitors in triple negative breast cancer

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-01-07 | E-GEOD-63584 | biostudies-arrayexpress

Targeting ACSS2 with a Transition-State Mimetic Inhibits Triple-Negative Breast Cancer Growth.

Project description:Acetyl-CoA is a vitally important and versatile metabolite used for many cellular processes including fatty acid synthesis, ATP production, and protein acetylation. Recent studies have shown that cancer cells upregulate acetyl-CoA synthetase 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in response to stresses such as low nutrient availability and hypoxia. Stressed cancer cells use ACSS2 as a means to exploit acetate as an alternative nutrient source. Genetic depletion of ACSS2 in tumors inhibits the growth of a wide variety of cancers. However, there are no studies on the use of an ACSS2 inhibitor to block tumor growth. In this study, we synthesized a small-molecule inhibitor that acts as a transition-state mimetic to block ACSS2 activity in vitro and in vivo. Pharmacologic inhibition of ACSS2 as a single agent impaired breast tumor growth. Collectively, our findings suggest that targeting ACSS2 may be an effective therapeutic approach for the treatment of patients with breast cancer. SIGNIFICANCE: These findings suggest that targeting acetate metabolism through ACSS2 inhibitors has the potential to safely and effectively treat a wide range of patients with cancer.

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Response and resistance to BET bromodomain inhibitors in triple negative breast cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-01-07 | GSE63584 | GEO