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Repressed Blautia-acetate immunological axis underlies breast cancer progression promoted by chronic stress.

ABSTRACT: Chronic stress is a known risk factor for breast cancer, yet the underlying mechanisms are unclear. This study explores the potential involvement of microbial and metabolic signals in chronic stress-promoted breast cancer progression, revealing that reduced abundances of Blautia and its metabolite acetate may contribute to this process. Treatment with Blautia and acetate increases antitumor responses of CD8⁺ T cells and reverses stress-promoted breast cancer progression in female mice. Patients with depression exhibit lower abundances of Blautia and acetate, and breast cancer female patients with depression display lower abundances of acetate, decreased numbers of tumor-infiltrating CD8⁺ T cells, and an increased risk of metastasis. These results suggest that Blautia-derived acetate plays a crucial role in modulating the immune response to breast cancer, and its reduction may contribute to chronic stress-promoted cancer progression. Our findings advance the understanding of microbial and metabolic signals implicated in cancer in patients with depression and may provide therapeutic options for female patients with breast cancer and depression.

SUBMITTER: Ye L

PROVIDER: S-EPMC10547687 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Repressed Blautia-acetate immunological axis underlies breast cancer progression promoted by chronic stress.

Ye Ling L Hou Yuanlong Y Hu Wanyu W Wang Hongmei H Yang Ruopeng R Zhang Qihan Q Feng Qiaoli Q Zheng Xiao X Yao Guangyu G Hao Haiping H

Nature communications 20231003 1

Chronic stress is a known risk factor for breast cancer, yet the underlying mechanisms are unclear. This study explores the potential involvement of microbial and metabolic signals in chronic stress-promoted breast cancer progression, revealing that reduced abundances of Blautia and its metabolite acetate may contribute to this process. Treatment with Blautia and acetate increases antitumor responses of CD8<sup>+</sup> T cells and reverses stress-promoted breast cancer progression in female mice ...[more]

PMID: 37789028

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Project description:Backgroundα5-nicotinic acetylcholine receptor (α5-nAChR) participates in chronic stress-promoted lung adenocarcinoma (LUAD) progression. Neuropilin and tolloid-like 2 (NETO2) contributes to fear expression and extinction, which is related to tumorigenesis. CHRNA5 (encoding α5-nAChR) gene profiling revealed a reduction in NETO2 expression following CHRNA5 knockdown. Nevertheless, the connection between α5-nAChR and NETO2 in LUAD progression induced by chronic stress remains unclear.MethodsRNA-Seq and bioinformatics database were used for analyzing the expression as well as correlation of α5-nAChR, together with NETO2 in LUAD. α5-nAChR and NETO2 expression were detected using immunohistochemistry in LUAD tissue microarrays, chronic restraint stress (CRS) and chronic unpredictable stress (CUMS) mice tissues. In lung adenocarcinoma A549 and H1299 cells, the expression of α5-nAChR, NETO2, p-CAMKII, p-STAT3 and vimentin induced by acetylcholine/nicotine was examined by western blot. The interaction of α5-nAChR with NETO2 in lung adenocarcinoma cells was detected by Co-immunoprecipitation assay and modeled using molecular docking. EdU assay and colony formation assay were conducted to evaluate cell proliferation, while wound healing assay as well as transwell assay assessed the migration and invasion of lung adenocarcinoma cells.Resultsα5-nAChR expression was related to NETO2 expression, low survival rate, staging as well as smoking status in LUAD dataset as well as tissue microarrays. The correlation between α5-nAChR and NETO2 was validated in nude mice xenograft tissues. α5-nAChR as well as NETO2 expression correlated in CRS and CUMS mice tissues. In vitro, acetylcholine/nicotine mediated NETO2, p-CAMKII, p-STAT3 and vimentin expression via α5-nAChR. α5-nAChR interacted with NETO2 as well as CAMKII in LUAD cells. α5-nAChR/NETO2 signaling contributed to LUAD cell proliferation, migration and invasion.ConclusionsThe above results uncover a new chronic stress-promoted LUAD signaling pathway: α5-nAChR/NETO2 axis contributes to chronic stress-promoted LUAD cell proliferation, migration and invasion.

Project description:Rationale: Psychological stress has been linked to cancer development and resistance to therapy by many epidemiological and clinical studies. Stress-induced immunosuppressive microenvironment by stress hormones, in particular glucocorticoids, has been extensively studied. However, the impacts of other stress-related neurotransmitters, such as serotonin (5-hydroxytryptamine, 5-HT), on cancer development just start to be revealed. Here, we aimed to identify novel neurotransmitters involved in stress-induced growth and dissemination of ovarian cancer (OC) and reveal the major underlying signaling pathway and the therapeutic significance. Methods: Through a genome-wide CRISPR/Cas9 knockout screen in the murine orthotopic model of ovarian carcinoma (OC), we identified candidate genes regulating the peritoneal dissemination of OC. Among them, we picked out HTR1E, one member of 5-HT receptor family specifically expressed in the ovary and endometrium in addition to brain. The correlation of HTR1E expression with OC progression was analyzed in OC patient specimen by quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry (IHC). Gain-of-function and loss-of-function analyses were performed to explore the functions of 5-HT/HTR1E signaling in OC growth and dissemination in vitro and in vivo. In addition, we investigated the therapeutic values of HTR1E specific agonist and small molecular inhibitors against HTR1E downstream factor SRC in a stressed murine OC xenograft model. Results: In OC patients, the HTR1E expression is dramatically decreased in peritoneal disseminated OC cells, which correlates with poor clinical outcome. Silence of HTR1E in OC cells greatly promotes cell proliferation and epithelial mesenchymal transition (EMT) by the activation of SRC-mediated downstream signaling pathways. Furthermore, chronic stress results in significantly decreased serotonin in the ovary and the enhanced OC growth and peritoneal dissemination in mice, which can be strongly inhibited by specific HTR1E agonist or the SRC inhibitor. Conclusions: We discovered the essential role of serotonin/HTR1E signaling in preventing the chronic psychological stress-promoted progression of OC, suggesting the potential therapeutic value of the HTR1E specific agonist and the SRC inhibitor for OC patients who are suffering from psychological stress.

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Repressed Blautia-acetate immunological axis underlies breast cancer progression promoted by chronic stress.

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Repressed Blautia-acetate immunological axis underlies breast cancer progression promoted by chronic stress.

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