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Acetyl-lysine Reader CECR2 Drives Breast Cancer Metastasis by Coordinating Macrophage Polarization and Immune Suppression [metastasis]

ABSTRACT: Purpose: Advanced breast cancer leads to significantly higher mortality due to metastasis. The goal of this work is to screen and study the deregulated epigenetic regulators to identify the novel targets for the treatment of metastatic breast cancer. Methods:RNA-Seq analysis of matched primary and metastatic breast samples to detect the deregulated epigenetic regulators. Live imaging system was applied to modulate metastatic tumor growth in vivo. Results: we identified that deregulated CECR2 was associated with breast cancer metastasis by RNA sequencing analysis of the matched primary and metastatic breast cancer samples from 13 patients. CECR2 knockout significantly decreased breast cancer metastasis in both immunocompromised and immunocompetent mice models. RNA-seq analysis showed that gene set "response to NF-κB signaling" was significantly decreased by CECR2 depletion in breast cancer cells. Mechanistically, CECR2 formed a complex with RELA on NF-κB target gene promoters to activate target gene expression. Furthermore, CECR2 played a key role in tumor associated macrophage recruitment and polarization, which regulates the antitumor immunity in microenvironment. Conclusions: our work identified and characterized a novel epigenetic regulator CECR2 in regulating breast cancer metastasis, and can serve as a potential target for the treatment of metastatic breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147995 | GEO | 2021/12/31

REPOSITORIES: GEO

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Acetyl-lysine Reader CECR2 Drives Breast Cancer Metastasis by Coordinating Macrophage Polarization and Immune Suppression [cell line]

Project description:Purpose: Advanced breast cancer leads to significantly higher mortality due to metastasis. The goal of this work is to screen and study the deregulated epigenetic regulators to identify the novel targets for the treatment of metastatic breast cancer. Methods:RNA-Seq analysis of matched primary and metastatic breast samples to detect the deregulated epigenetic regulators. Live imaging system was applied to modulate metastatic tumor growth in vivo. Results: we identified that deregulated CECR2 was associated with breast cancer metastasis by RNA sequencing analysis of the matched primary and metastatic breast cancer samples from 13 patients. CECR2 knockout significantly decreased breast cancer metastasis in both immunocompromised and immunocompetent mice models. RNA-seq analysis showed that gene set "response to NF-κB signaling" was significantly decreased by CECR2 depletion in breast cancer cells. Mechanistically, CECR2 formed a complex with RELA on NF-κB target gene promoters to activate target gene expression. Furthermore, CECR2 played a key role in tumor associated macrophage recruitment and polarization, which regulates the antitumor immunity in microenvironment. Conclusions: our work identified and characterized a novel epigenetic regulator CECR2 in regulating breast cancer metastasis, and can serve as a potential target for the treatment of metastatic breast cancer.

2021-12-31 | GSE147993 | GEO

CECR2 Drives Breast Cancer Metastasis by Suppressing Macrophage Inflammatory Responses

Project description:Purpose: Metastasis are responsible for the most majority of cancer-related deaths due to the lack of effective targeted therapies. Therefore, specific targets which tackle that complex process are needed to improve the therapeutic outcomes of metastatic breast cancer. Methods: ATAC-Seq analysis of CECR2 knockout and control LM2 cells. Results: CECR2 knockout regulate chromatin accessibility of NF-kB target genes . Conclusions: Our work confirmed that CECR2 knockout attenuates chromatin accessibility at promoters or enhancers of the downstream NF-kB target genes.

2022-01-21 | GSE185647 | GEO

A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation [scRNA-seq high fat diet]

Project description:Cancer cells outgrowing in distant organs of metastasis rewire their metabolism to fuel on the available nutrients. While this is often considered an adaptive pressure limiting metastasis formation, some nutrients available at the metastatic site naturally or through changes in organ physiology may inherently promote metastatic growth. We find that the lung, a frequent site of metastasis, is a lipid-rich environment. Moreover, we observe that pathological conditions such as pre-metastatic niche formation and obesity further increase the availability of the fatty acid palmitate in the lung. We find that targeting palmitate processing inhibits spheroid growth in vitro and metastasis formation in lean and obese mice. Mechanistically, we discover that breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1a)-dependent manner. Lysine acetyltransferase 2a (KAT2a), whose expression is promoted by palmitate availability, relies on the available acetyl-CoA to acetylate the NF-κB subunit p65. This favors nuclear location of p65 and activates a pro-metastatic transcriptional program. Accordingly, deletion of KAT2a phenocopies CPT1a silencing in vitro as well as in vivo and patients with breast cancer show co-expression of both proteins in metastases across palmitate-rich metastatic sites. In conclusion, we find that palmitate-rich environments foster metastasis growth by increasing p65 acetylation resulting in elevated NF-κB signaling.

2022-10-28 | GSE216695 | GEO

MEST Promotes Lung Cancer Invasion and Metastasis by Interacting with VCP to Activate NF-κB Signaling

Project description:Active cell invasion is a hallmark of metastatic cancer, leading to unfavorable clinical outcome. We here established high-invasive lung cancer cell models, A549-i8 and H1299-i8, and identified mesoderm-specific transcript (MEST) as a novel invasive regulator for lung cancer. MEST overexpression promoted the metastasis of lung cancer cells in vivo and in vitro by activating NF-κB signaling. MEST enhanced the interaction of VCP with IκBα, which accelerated IκBα degradation and NF-κB activation. Such an acceleration could be abrogated by VCP silencing, indicating that MEST is an upstream regulator to induce the sequential VCP/IκBα/NF-κB signaling. Furthermore, high MEST and VCP expressions were associated with poor survival of lung cancer patients. Collectively, we demonstrated that MEST plays an important role in driving invasion and metastasis of lung cancer by interacting with VCP, coordinating IκBα/NF-κB pathway. Targeting MEST/VCP/IκBα/NF-κB signaling may represent a promising therapeutic strategy for lung cancer.

2021-06-02 | PXD026409 | iProX

Rhodes2019 - Immune-Mediated theory of Metastasis

Project description:Abstract: Accumulating experimental and clinical evidence suggest that the immune response to cancer is not exclusively anti-tumor. Indeed, the pro-tumor roles of the immune system - as suppliers of growth and pro-angiogenic factors or defenses against cytotoxic immune attacks, for example - have been long appreciated, but relatively few theoretical works have considered their effects. Inspired by the recently proposed "immune-mediated" theory of metastasis, we develop a mathematical model for tumor-immune interactions at two anatomically distant sites, which includes both anti- and pro-tumor immune effects, and the experimentally observed tumor-induced phenotypic plasticity of immune cells (tumor "education" of the immune cells). Upon confrontation of our model to experimental data, we use it to evaluate the implications of the immune-mediated theory of metastasis. We find that tumor education of immune cells may explain the relatively poor performance of immunotherapies, and that many metastatic phenomena, including metastatic blow-up, dormancy, and metastasis to sites of injury, can be explained by the immune-mediated theory of metastasis. Our results suggest that further work is warranted to fully elucidate the pro-tumor effects of the immune system in metastatic cancer.

2020-03-28 | BIOMD0000000926 | BioModels

The function and mechanism about how ORAOV1-B potentiates the OSCC metastasis.

Project description:Lymph node metastasis, a powerful prognostic indicator of oral squamous cell carcinoma (OSCC), is chiefly responsible for cancer death. Long non-coding RNA (lncRNA) is recently addressed to significantly account for modulating OSCC metastasis. Here, we identified a novel alternative splice of Oral Cancer Overexpressed 1 (ORAOV1), ORAOV1-B, which was subsequently validated as an lncRNA and correlated with OSCC lymph node metastasis; significantly increased invasion and migration were observed in ORAOV1-B-overexpressed OSCC cells; In the metastatic model, ORAOV1-B also significantly contributed to OSCC-related lung metastasis. cDNA microarrays was performed to compare up- or down-regulated genes in EV and ORAOV1-B sets of OSCC, which suggested TNFα as a potential downstream of ORAOV1-B and the upregulation of pro-inflammatory genes, indicating the activation of NF-κB pathway. In summary, the novel splice variant ORAOV1-B is an lncRNA, which significantly potentiates OSCC invasion and metastasis by binding to Hsp90 and activating the NF-κB-TNFα loop. Our study implies that ORAOV1-B might serve as an attractive OSCC metastasis intervention target.

2020-03-04 | GSE145599 | GEO

CECR2 Drives Breast Cancer Metastasis by Suppressing Macrophage Inflammatory Responses

Project description:CECR2 Drives Breast Cancer Metastasis by Suppressing Macrophage Inflammatory Responses

| PRJNA770272 | ENA

A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation [RNA-Seq]

Project description:Cancer cells outgrowing in distant organs of metastasis rewire their metabolism to fuel on the available nutrients. While this is often considered an adaptive pressure limiting metastasis formation, some nutrients available at the metastatic site naturally or through changes in organ physiology may inherently promote metastatic growth. We find that the lung, a frequent site of metastasis, is a lipid-rich environment. Moreover, we observe that pathological conditions such as pre-metastatic niche formation and obesity further increase the availability of the fatty acid palmitate in the lung. We find that targeting palmitate processing inhibits spheroid growth in vitro and metastasis formation in lean and obese mice. Mechanistically, we discover that breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1a)-dependent manner. Lysine acetyltransferase 2a (KAT2a), whose expression is promoted by palmitate availability, relies on the available acetyl-CoA to acetylate the NF-B subunit p65. This favors nuclear location of p65 and activates a pro-metastatic transcriptional program. Accordingly, deletion of KAT2a phenocopies CPT1a silencing in vitro as well as in vivo and patients with breast cancer show co-expression of both proteins in metastases across palmitate-rich metastatic sites. In conclusion, we find that palmitate-rich environments foster metastasis growth by increasing p65 acetylation resulting in elevated NF-B signaling.

2022-06-01 | GSE197134 | GEO

A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation [scRNA-seq]

Project description:Cancer cells outgrowing in distant organs of metastasis rewire their metabolism to fuel on the available nutrients. While this is often considered an adaptive pressure limiting metastasis formation, some nutrients available at the metastatic site naturally or through changes in organ physiology may inherently promote metastatic growth. We find that the lung, a frequent site of metastasis, is a lipid-rich environment. Moreover, we observe that pathological conditions such as pre-metastatic niche formation and obesity further increase the availability of the fatty acid palmitate in the lung. We find that targeting palmitate processing inhibits spheroid growth in vitro and metastasis formation in lean and obese mice. Mechanistically, we discover that breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1a)-dependent manner. Lysine acetyltransferase 2a (KAT2a), whose expression is promoted by palmitate availability, relies on the available acetyl-CoA to acetylate the NF-B subunit p65. This favors nuclear location of p65 and activates a pro-metastatic transcriptional program. Accordingly, deletion of KAT2a phenocopies CPT1a silencing in vitro as well as in vivo and patients with breast cancer show co-expression of both proteins in metastases across palmitate-rich metastatic sites. In conclusion, we find that palmitate-rich environments foster metastasis growth by increasing p65 acetylation resulting in elevated NF-B signaling.

2022-06-01 | GSE196992 | GEO

A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation [ChIP-seq]

Project description:Cancer cells outgrowing in distant organs of metastasis rewire their metabolism to fuel on the available nutrients. While this is often considered an adaptive pressure limiting metastasis formation, some nutrients available at the metastatic site naturally or through changes in organ physiology may inherently promote metastatic growth. We find that the lung, a frequent site of metastasis, is a lipid-rich environment. Moreover, we observe that pathological conditions such as pre-metastatic niche formation and obesity further increase the availability of the fatty acid palmitate in the lung. We find that targeting palmitate processing inhibits spheroid growth in vitro and metastasis formation in lean and obese mice. Mechanistically, we discover that breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1a)-dependent manner. Lysine acetyltransferase 2a (KAT2a), whose expression is promoted by palmitate availability, relies on the available acetyl-CoA to acetylate the NF-B subunit p65. This favors nuclear location of p65 and activates a pro-metastatic transcriptional program. Accordingly, deletion of KAT2a phenocopies CPT1a silencing in vitro as well as in vivo and patients with breast cancer show co-expression of both proteins in metastases across palmitate-rich metastatic sites. In conclusion, we find that palmitate-rich environments foster metastasis growth by increasing p65 acetylation resulting in elevated NF-B signaling.

2022-06-01 | GSE196991 | GEO

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